Genetic Variant USH1C:p.Pro396Pro (chr11-17520892-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_153676.4(USH1C):c.1188A>G(p.Pro396Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,522 control chromosomes in the GnomAD database, including 270,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21597 hom., cov: 32)

Exomes 𝑓: 0.58 ( 248931 hom. )

Consequence

USH1C
NM_153676.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.07

Publications

27 publications found

Variant links:

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 11-17520892-T-C is Benign according to our data. Variant chr11-17520892-T-C is described in ClinVar as Benign. ClinVar VariationId is 47976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	NM_153676.4	MANE Select	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 21	NP_005700.2
USH1C	NM_001440679.1		c.1221A>G	p.Pro407Pro	synonymous	Exon 14 of 22	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1188A>G	p.Pro396Pro	synonymous	Exon 14 of 21	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.1131A>G	p.Pro377Pro	synonymous	Exon 13 of 20	ENSP00000436934.1

Frequencies

GnomAD3 genomes

AF:

0.521

AC:

79131

AN:

151920

Hom.:

21579

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.582

Gnomad EAS

AF:

0.660

Gnomad SAS

AF:

0.529

Gnomad FIN

AF:

0.557

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.587

Gnomad OTH

AF:

0.519

GnomAD2 exomes

AF:

0.576

AC:

144888

AN:

251476

AF XY:

0.573

show subpopulations

Gnomad AFR exome

AF:

0.334

Gnomad AMR exome

AF:

0.670

Gnomad ASJ exome

AF:

0.586

Gnomad EAS exome

AF:

0.661

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.583

Gnomad OTH exome

AF:

0.580

GnomAD4 exome

AF:

0.581

AC:

848790

AN:

1461484

Hom.:

248931

Cov.:

AF XY:

0.580

AC XY:

421370

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.333

AC:

11140

AN:

33474

American (AMR)

AF:

0.664

AC:

29680

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.577

AC:

15080

AN:

26132

East Asian (EAS)

AF:

0.674

AC:

26766

AN:

39700

South Asian (SAS)

AF:

0.523

AC:

45085

AN:

86250

European-Finnish (FIN)

AF:

0.574

AC:

30632

AN:

53406

Middle Eastern (MID)

AF:

0.501

AC:

2886

AN:

5760

European-Non Finnish (NFE)

AF:

0.588

AC:

653137

AN:

1111656

Other (OTH)

AF:

0.569

AC:

34384

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

20684

41367

62051

82734

103418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17902

35804

53706

71608

89510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.521

AC:

79190

AN:

152038

Hom.:

21597

Cov.:

AF XY:

0.523

AC XY:

38875

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.345

AC:

14302

AN:

41448

American (AMR)

AF:

0.610

AC:

9323

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

2018

AN:

3468

East Asian (EAS)

AF:

0.660

AC:

3409

AN:

5162

South Asian (SAS)

AF:

0.529

AC:

2546

AN:

4814

European-Finnish (FIN)

AF:

0.557

AC:

5901

AN:

10600

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.587

AC:

39861

AN:

67960

Other (OTH)

AF:

0.521

AC:

1100

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1849

3698

5547

7396

9245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.560

Hom.:

38040

Bravo

AF:

0.516

Asia WGS

AF:

0.580

AC:

2015

AN:

3478

EpiCase

AF:

0.570

EpiControl

AF:

0.564

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 24, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 1C

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive nonsyndromic hearing loss 18A

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.98

(source)

DANN

Benign

0.43

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over