2-70301741-G-T

Variant names:

• chr2-70301741-G-T
• rs112790117
• NM_001329752.2:c.271C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001329752.2(FAM136A):​c.271C>A​(p.Arg91Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 0 publications found

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]

FAM136A Gene-Disease associations (from GenCC):

• Meniere disease

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000233849 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11866182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329752.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM136A	NM_001329752.2	MANE Select	c.271C>A	p.Arg91Ser	missense	Exon 1 of 3	NP_001316681.1	E7EQY1
	FAM136A	NM_001329753.2		c.271C>A	p.Arg91Ser	missense	Exon 1 of 3	NP_001316682.1
	FAM136A	NM_032822.3		c.87+184C>A		intron	N/A	NP_116211.2	Q96C01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM136A	ENST00000430566.6	TSL:3 MANE Select	c.271C>A	p.Arg91Ser	missense	Exon 1 of 3	ENSP00000397269.1	E7EQY1
	FAM136A	ENST00000037869.8	TSL:1	c.87+184C>A		intron	N/A	ENSP00000037869.3	Q96C01
	FAM136A	ENST00000460307.1	TSL:1	n.133-138C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 138030 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.3
DANN	Benign	0.95
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.082
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.030
Sift	Benign	0.032	D
Sift4G	Uncertain	0.025	D
Vest4		0.36
MutPred		0.43		Gain of phosphorylation at R91 (P = 0.0512)
MVP		0.014
ClinPred		0.11	T
GERP RS		1.7
PromoterAI		0.015	Neutral
gMVP		0.11
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: rs112790117; hg19: chr2-70528873;