rs2230644

Variant names:

• chr12-15669817-A-G
• rs2230644
• NM_004447.6:c.213T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004447.6(EPS8):​c.213T>C​(p.Thr71Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,595,590 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (23 hom.)
• Consequence: EPS8 NM_004447.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.350
• Publications: 2 publications found

Genes affected

EPS8 (HGNC:3420): (EGFR pathway substrate 8, signaling adaptor) This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

EPS8 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 102

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-15669817-A-G is Benign according to our data. Variant chr12-15669817-A-G is described in ClinVar as Benign. ClinVar VariationId is 517549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00959 (1461/152340) while in subpopulation AFR AF = 0.0328 (1364/41572). AF 95% confidence interval is 0.0314. There are 31 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004447.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	NM_004447.6	MANE Select	c.213T>C	p.Thr71Thr	synonymous	Exon 5 of 21	NP_004438.3
	EPS8	NM_001413831.1		c.213T>C	p.Thr71Thr	synonymous	Exon 5 of 22	NP_001400760.1
	EPS8	NM_001413832.1		c.213T>C	p.Thr71Thr	synonymous	Exon 6 of 22	NP_001400761.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8	ENST00000281172.10	TSL:1 MANE Select	c.213T>C	p.Thr71Thr	synonymous	Exon 5 of 21	ENSP00000281172.5
	EPS8	ENST00000543468.5	TSL:1	n.213T>C		non_coding_transcript_exon	Exon 5 of 20	ENSP00000445985.1
	EPS8	ENST00000642939.1		c.264T>C	p.Thr88Thr	synonymous	Exon 7 of 23	ENSP00000495312.1

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1460 AN: 152222 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00278 AC: 656 AN: 236078 AF XY: 0.00218

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00102 AC: 1465 AN: 1443250 Hom.: 23 Cov.: 31 AF XY: 0.000911 AC XY: 653 AN XY: 717100

African (AFR) AF: 0.0321 AC: 1039 AN: 32410

American (AMR) AF: 0.00218 AC: 87 AN: 39916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25018

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39494

South Asian (SAS) AF: 0.0000719 AC: 6 AN: 83416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52894

Middle Eastern (MID) AF: 0.00177 AC: 10 AN: 5660

European-Non Finnish (NFE) AF: 0.000143 AC: 158 AN: 1104808

Other (OTH) AF: 0.00275 AC: 164 AN: 59634

GnomAD4 genome AF: 0.00959 AC: 1461 AN: 152340 Hom.: 31 Cov.: 33 AF XY: 0.00856 AC XY: 638 AN XY: 74508

African (AFR) AF: 0.0328 AC: 1364 AN: 41572

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68030

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00852 Hom.: 18

Bravo AF: 0.0109

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.3
DANN	Benign	0.78
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2230644; hg19: chr12-15822751;