2-70297444-C-G

Variant names:

• chr2-70297444-C-G
• rs75086964
• NM_001329752.2:c.583G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP4_Strong BP6

The NM_001329752.2(FAM136A):​c.583G>C​(p.Asp195His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM136A NM_001329752.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.20
• Publications: 11 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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.010998726).
• BP6: Variant 2-70297444-C-G is Benign according to our data. Variant chr2-70297444-C-G is described in ClinVar as Benign. ClinVar VariationId is 3055771.Status of the report is no_assertion_criteria_provided, 0 stars.

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.583G>C	p.Asp195His	missense	Exon 3 of 3	NP_001316681.1	E7EQY1
	FAM136A	NM_001329753.2		c.517G>C	p.Asp173His	missense	Exon 3 of 3	NP_001316682.1
	FAM136A	NM_032822.3		c.262G>C	p.Asp88His	missense	Exon 3 of 3	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.583G>C	p.Asp195His	missense	Exon 3 of 3	ENSP00000397269.1	E7EQY1
	FAM136A	ENST00000037869.8	TSL:1	c.262G>C	p.Asp88His	missense	Exon 3 of 3	ENSP00000037869.3	Q96C01
	FAM136A	ENST00000460307.1	TSL:1	n.930G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3253 AN: 128200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0551

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.0295

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0115

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0284

GnomAD2 exomes AF: 0.00278 AC: 606 AN: 218350 AF XY: 0.00250

Gnomad AFR exome AF: 0.000791

Gnomad AMR exome AF: 0.00760

Gnomad ASJ exome AF: 0.00393

Gnomad EAS exome AF: 0.00159

Gnomad FIN exome AF: 0.000906

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00260

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0681 AC: 71351 AN: 1047294 Hom.: 0 Cov.: 39 AF XY: 0.0670 AC XY: 35262 AN XY: 526586

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0236 AC: 663 AN: 28100

American (AMR) AF: 0.116 AC: 3950 AN: 33928

Ashkenazi Jewish (ASJ) AF: 0.0610 AC: 1197 AN: 19626

East Asian (EAS) AF: 0.0445 AC: 1335 AN: 29972

South Asian (SAS) AF: 0.0358 AC: 2539 AN: 70904

European-Finnish (FIN) AF: 0.0239 AC: 1055 AN: 44166

Middle Eastern (MID) AF: 0.0252 AC: 117 AN: 4642

European-Non Finnish (NFE) AF: 0.0753 AC: 58084 AN: 771330

Other (OTH) AF: 0.0540 AC: 2411 AN: 44626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0254 AC: 3255 AN: 128314 Hom.: 0 Cov.: 33 AF XY: 0.0267 AC XY: 1677 AN XY: 62920

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0145 AC: 535 AN: 37010

American (AMR) AF: 0.0334 AC: 417 AN: 12480

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 92 AN: 2832

East Asian (EAS) AF: 0.0296 AC: 123 AN: 4160

South Asian (SAS) AF: 0.0228 AC: 94 AN: 4120

European-Finnish (FIN) AF: 0.0249 AC: 228 AN: 9154

Middle Eastern (MID) AF: 0.00820 AC: 2 AN: 244

European-Non Finnish (NFE) AF: 0.0300 AC: 1674 AN: 55786

Other (OTH) AF: 0.0280 AC: 51 AN: 1820

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0289 Hom.: 0

ExAC AF: 0.0572 AC: 6940

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FAM136A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.87
MPC		0.41
ClinPred		0.026	T
GERP RS		5.0
Varity_R		0.88
gMVP		0.75
Mutation Taster		=8/92	disease causing

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: rs75086964; hg19: chr2-70524576; COSMIC: COSV50682337; COSMIC: COSV50682337;