chr1-6451841-G-A

Variant names:

• chr1-6451841-G-A
• rs142850918
• NM_031475.3:c.2070G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.42
• Publications: 0 publications found

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):

• autosomal recessive nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• 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)

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.2070G>A	p.Ser690Ser	synonymous	Exon 10 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.2007G>A	p.Ser669Ser	synonymous	Exon 12 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.1980G>A	p.Ser660Ser	synonymous	Exon 11 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.2070G>A	p.Ser690Ser	synonymous	Exon 10 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000461727.6	TSL:1	c.372G>A	p.Ser124Ser	synonymous	Exon 5 of 8	ENSP00000465308.1	B1AK53-2
	ESPN	ENST00000636330.1	TSL:5	c.2070G>A	p.Ser690Ser	synonymous	Exon 10 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152186 Hom.: 5 Cov.: 32

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

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.: 46 Cov.: 32 AF XY: 0.00614 AC XY: 4455 AN XY: 725574

African (AFR) AF: 0.00108 AC: 36 AN: 33444

American (AMR) AF: 0.00254 AC: 113 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 84 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 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: 48 AN: 5646

European-Non Finnish (NFE) AF: 0.00705 AC: 7835 AN: 1111226

Other (OTH) AF: 0.00559 AC: 337 AN: 60264

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00510 AC XY: 380 AN XY: 74474

African (AFR) AF: 0.00168 AC: 70 AN: 41570

American (AMR) AF: 0.00307 AC: 47 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.00782 AC: 83 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00770 AC: 524 AN: 68012

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00689 Hom.: 3

Bravo AF: 0.00466

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 36;C5231434:Usher syndrome, type 1M (1)
-	-	1	ESPN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		-1.4
PromoterAI		-0.017	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs142850918; hg19: chr1-6511901;