rs142850918

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_031475.3(ESPN):c.2070G>A(p.Ser690Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,611,192 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 46 hom. )

Consequence

ESPN
NM_031475.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.42

Publications

0 publications found

Variant links:

Genes affected

ESPN (HGNC:13281): (espin) This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

ESPN Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 36
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome, type 1M
Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ESPN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 1-6451841-G-A is Benign according to our data. Variant chr1-6451841-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226635.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 = 0.00497 (757/152304) while in subpopulation NFE AF = 0.0077 (524/68012). AF 95% confidence interval is 0.00716. There are 5 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3 link	c.2070G>A	p.Ser690Ser	synonymous_variant	Exon 10 of 13	ENST00000645284.1	NP_113663.2	B1AK53-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1 link	c.2070G>A	p.Ser690Ser	synonymous_variant	Exon 10 of 13		NM_031475.3	ENSP00000496593.1		B1AK53-1

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00782

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00770

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00504

AC:

1225

AN:

242892

AF XY:

0.00533

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00385

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00672

Gnomad NFE exome

AF:

0.00764

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00618

AC:

9011

AN:

1458888

Hom.:

Cov.:

AF XY:

0.00614

AC XY:

4455

AN XY:

725574

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33444

American (AMR)

AF:

0.00254

AC:

113

AN:

44506

Ashkenazi Jewish (ASJ)

AF:

0.00322

AC:

AN:

26062

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39636

South Asian (SAS)

AF:

0.00249

AC:

214

AN:

85846

European-Finnish (FIN)

AF:

0.00656

AC:

343

AN:

52258

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00705

AC:

7835

AN:

1111226

Other (OTH)

AF:

0.00559

AC:

337

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

626

1251

1877

2502

3128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.00497

AC:

757

AN:

152304

Hom.:

Cov.:

AF XY:

0.00510

AC XY:

380

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

41570

American (AMR)

AF:

0.00307

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00782

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00770

AC:

524

AN:

68012

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

152

190

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:

0.00689

Hom.:

Bravo

AF:

0.00466

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Nov 18, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ESPN: BS2 -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Mar 27, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ser690Ser in Exon 10 of ESPN: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.8% (53/7014) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142850918). -

Autosomal recessive nonsyndromic hearing loss 36;C5231434:Usher syndrome, type 1M

Benign:1

Aug 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ESPN-related disorder

Benign:1

Nov 12, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

-1.4

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: 35

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over