dbSNP rs149202009: WHRN:c.1166+18G>A (chr9-114426193-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015404.4(WHRN):c.1166+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,611,748 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 35 hom. )

Consequence

WHRN
NM_015404.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.72

Publications

2 publications found

Variant links:

Genes affected

WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

WHRN Gene-Disease associations (from GenCC):

Usher syndrome type 2D
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive nonsyndromic hearing loss 31
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WHRN links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_015404.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 9-114426193-C-T is Benign according to our data. Variant chr9-114426193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00432 (658/152232) while in subpopulation NFE AF = 0.00731 (497/68008). AF 95% confidence interval is 0.00678. There are 2 homozygotes in GnomAd4. There are 287 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WHRN	NM_015404.4	MANE Select	c.1166+18G>A	intron	N/A	NP_056219.3	Q9P202-1
WHRN	NM_001173425.2		c.1166+18G>A	intron	N/A	NP_001166896.1
WHRN	NM_001083885.3		c.17+18G>A	intron	N/A	NP_001077354.2	Q9P202-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WHRN	ENST00000362057.4	TSL:1 MANE Select	c.1166+18G>A	intron	N/A	ENSP00000354623.3	Q9P202-1
WHRN	ENST00000265134.10	TSL:1	c.17+18G>A	intron	N/A	ENSP00000265134.6	Q9P202-3
WHRN	ENST00000866780.1		c.1166+18G>A	intron	N/A	ENSP00000536839.1

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

658

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00575

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00731

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00467

AC:

1171

AN:

250518

AF XY:

0.00478

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00983

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00735

Gnomad NFE exome

AF:

0.00665

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00587

AC:

8565

AN:

1459516

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

4274

AN XY:

726044

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33414

American (AMR)

AF:

0.00134

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

290

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00260

AC:

224

AN:

86166

European-Finnish (FIN)

AF:

0.00717

AC:

381

AN:

53116

Middle Eastern (MID)

AF:

0.000964

AC:

AN:

4150

European-Non Finnish (NFE)

AF:

0.00652

AC:

7255

AN:

1111902

Other (OTH)

AF:

0.00545

AC:

328

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

493

985

1478

1970

2463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00432

AC:

658

AN:

152232

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

287

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41544

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00575

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00731

AC:

497

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00584

Hom.:

Bravo

AF:

0.00377

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Usher syndrome type 2D;C1846839:Autosomal recessive nonsyndromic hearing loss 31 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0030

(source)

DANN

Benign

0.61

PhyloP100

-4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over