chr2-70301656-C-T

Variant names:

• chr2-70301656-C-T
• rs552744004
• NM_001329752.2:c.356G>A

Variant summary

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

The NM_001329752.2(FAM136A):​c.356G>A​(p.Trp119*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM136A NM_001329752.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.936
• 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 2 ACMG points.

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

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.356G>A	p.Trp119*	stop_gained	Exon 1 of 3	NP_001316681.1	E7EQY1
	FAM136A	NM_001329753.2		c.342+14G>A		intron	N/A	NP_001316682.1
	FAM136A	NM_032822.3		c.87+269G>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.356G>A	p.Trp119*	stop_gained	Exon 1 of 3	ENSP00000397269.1	E7EQY1
	FAM136A	ENST00000037869.8	TSL:1	c.87+269G>A		intron	N/A	ENSP00000037869.3	Q96C01
	FAM136A	ENST00000460307.1	TSL:1	n.133-53G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383030 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 682386

African (AFR) AF: 0.00 AC: 0 AN: 31580

American (AMR) AF: 0.0000280 AC: 1 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078402

Other (OTH) AF: 0.00 AC: 0 AN: 57870

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Pathogenic	30
DANN	Benign	0.90
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.015	N
PhyloP100		-0.94
Vest4		0.017
GERP RS		-1.4
PromoterAI		-0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=138/62	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs552744004; hg19: chr2-70528788;