rs748392606

Variant names:

• chr2-70300959-C-G
• rs748392606
• NM_001329752.2:c.430G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-70300959-C-G
• chr2-70300959-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001329752.2(FAM136A):​c.430G>C​(p.Ala144Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM136A	NM_001329752.2	c.430G>C	p.Ala144Pro	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.430G>C	p.Ala144Pro	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: 251118 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460030 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.80		Gain of loop (P = 0.0312);.;.;
MVP		0.11
MPC		0.43
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.74

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: rs748392606; hg19: chr2-70528091;