Variant 20-2579147-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_080751.3(TMC2):c.647A>G(p.Lys216Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMC2
NM_080751.3 missense, splice_region

Scores

Splicing: ADA: 0.6031

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.89

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMC2	NM_080751.3 linkuse as main transcript	c.647A>G	p.Lys216Arg	missense_variant, splice_region_variant	6/20	ENST00000358864.2	NP_542789.2
TMC2	XM_005260660.5 linkuse as main transcript	c.722A>G	p.Lys241Arg	missense_variant, splice_region_variant	4/18		XP_005260717.1
TMC2	XR_001754152.2 linkuse as main transcript	n.856A>G		splice_region_variant, non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC2	ENST00000358864.2 linkuse as main transcript	c.647A>G	p.Lys216Arg	missense_variant, splice_region_variant	6/20	1	NM_080751.3	ENSP00000351732	P1	Q8TDI7-1
TMC2	ENST00000644205.1 linkuse as main transcript	n.806A>G		splice_region_variant, non_coding_transcript_exon_variant	4/15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1404196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702276

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.647A>G (p.K216R) alteration is located in exon 6 (coding exon 6) of the TMC2 gene. This alteration results from a A to G substitution at nucleotide position 647, causing the lysine (K) at amino acid position 216 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.0031

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.27

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.69

MutPred

0.46

Loss of methylation at K221 (P = 0.1651);

MVP

0.66

MPC

0.17

ClinPred

0.96

GERP RS

4.9

Varity_R

0.23

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.60

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over