2-70300866-C-G

Variant names:

• chr2-70300866-C-G
• rs142320110
• NM_001329752.2:c.523G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001329752.2(FAM136A):​c.523G>C​(p.Val175Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 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: 𝑓 0.0000066 (0 hom., cov: 33)
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM136A	NM_001329752.2	c.523G>C	p.Val175Leu	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.523G>C	p.Val175Leu	missense_variant	Exon 2 of 3	3	NM_001329752.2	ENSP00000397269.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N;D;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.019	D;T;T
Sift4G	Uncertain	0.011	D;D;.
Polyphen		0.97	D;.;.
Vest4		0.86
MutPred		0.78		Gain of disorder (P = 0.1183);.;.;
MVP		0.048
MPC		0.11
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Varity_R		0.61
gMVP		0.62

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: rs142320110; hg19: chr2-70527998;