rs781046919

Variant names:

• chr2-70300967-C-G
• rs781046919
• NM_001329752.2:c.422G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-70300967-C-G
• chr2-70300967-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001329752.2(FAM136A):​c.422G>C​(p.Arg141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,354 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.977

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM136A	NM_001329752.2	c.422G>C	p.Arg141Pro	missense_variant	Exon 2 of 3	ENST00000430566.6	NP_001316681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM136A	ENST00000430566.6	c.422G>C	p.Arg141Pro	missense_variant	Exon 2 of 3	3	NM_001329752.2	ENSP00000397269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250986 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459354 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.065	T;D;D
Sift4G	Uncertain	0.038	D;D;.
Polyphen		0.86	P;.;.
Vest4		0.78
MutPred		0.64		Loss of MoRF binding (P = 0.001);.;.;
MVP		0.10
MPC		0.39
ClinPred		0.93	D
GERP RS		3.1
Varity_R		0.89
gMVP		0.69

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: rs781046919; hg19: chr2-70528099;