Variant 20-2558641-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_080751.3(TMC2):c.268G>A(p.Glu90Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,573,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

TMC2
NM_080751.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.13

Variant links:

Genes affected

TMC2 (HGNC:16527): (transmembrane channel like 2) This gene encodes a transmembrane protein that is necesssary for mechanotransduction in cochlear hair cells of the inner ear. Mutations in this gene may underlie hereditary disorders of balance and hearing. [provided by RefSeq, Aug 2015]

TMC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021631181).

BP6

Variant 20-2558641-G-A is Benign according to our data. Variant chr20-2558641-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2255469.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMC2	NM_080751.3 linkuse as main transcript	c.268G>A	p.Glu90Lys	missense_variant	3/20	ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5 linkuse as main transcript	c.343G>A	p.Glu115Lys	missense_variant	1/18		XP_005260717.1
TMC2	XR_001754152.2 linkuse as main transcript	n.477G>A		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2 linkuse as main transcript	c.268G>A	p.Glu90Lys	missense_variant	3/20	1	NM_080751.3	ENSP00000351732	P1	Q8TDI7-1
TMC2	ENST00000644205.1 linkuse as main transcript	n.427G>A		non_coding_transcript_exon_variant	1/15

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD3 exomes

AF:

0.0000323

AC:

AN:

185664

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

98874

show subpopulations

Gnomad AFR exome

AF:

0.000463

Gnomad AMR exome

AF:

0.0000374

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:

0.0000232

AC:

AN:

1421492

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

703066

show subpopulations

Gnomad4 AFR exome

AF:

0.000765

Gnomad4 AMR exome

AF:

0.0000266

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000366

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.000249

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000841

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000686

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000832

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.082

DANN

Benign

0.71

DEOGEN2

Benign

0.0019

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.19

M_CAP

Benign

0.0036

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.12

REVEL

Benign

0.014

Sift

Benign

1.0

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.13

MVP

0.048

MPC

0.14

ClinPred

0.012

GERP RS

-7.9

Varity_R

0.029

gMVP

0.087

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over