chr2-70297445-G-A

Variant names:

• chr2-70297445-G-A
• rs2618235
• NM_001329752.2:c.582C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001329752.2(FAM136A):​c.582C>T​(p.Asn194Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,607,534 control chromosomes in the GnomAD database, including 48,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.26 (4538 hom., cov: 33)
  • Exomes 𝑓: 0.29 (43979 hom.)
• Consequence: FAM136A NM_001329752.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.777

Genes affected

FAM136A (HGNC:25911): (family with sequence similarity 136 member A) This gene encodes a mitochondrially localized protein that is highly conserved across species. The gene is expressed in a variety of tissues including human lymphoblast cells and rat neurosensorial epithelium of the cristaampullaris. A mutation in this gene has been associated with familial Meniere's disease, a chronic disorder of the inner ear. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-70297445-G-A is Benign according to our data. Variant chr2-70297445-G-A is described in ClinVar as [Benign]. Clinvar id is 3059710.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.777 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM136A	NM_001329752.2	c.582C>T	p.Asn194Asn	synonymous_variant	Exon 3 of 3	ENST00000430566.6	NP_001316681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM136A	ENST00000430566.6	c.582C>T	p.Asn194Asn	synonymous_variant	Exon 3 of 3	3	NM_001329752.2	ENSP00000397269.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39427 AN: 150872 Hom.: 4546 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.258

GnomAD3 exomes AF: 0.284 AC: 71114 AN: 250460 Hom.: 8961 AF XY: 0.287 AC XY: 38879 AN XY: 135318

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.353

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.294 AC: 427723 AN: 1456542 Hom.: 43979 Cov.: 65 AF XY: 0.294 AC XY: 212976 AN XY: 724620

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.261 AC: 39424 AN: 150992 Hom.: 4538 Cov.: 33 AF XY: 0.266 AC XY: 19622 AN XY: 73770

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.256

Alfa AF: 0.279 Hom.: 2279

Asia WGS AF: 0.312 AC: 1085 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FAM136A-related disorder Benign:1

Jun 22, 2020

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	-0.68
CADD	Benign	0.50
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs2618235; hg19: chr2-70524577; COSMIC: COSV50682662; COSMIC: COSV50682662;