chr20-2558711-C-T

Variant names:

• chr20-2558711-C-T
• NM_080751.3:c.338C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080751.3(TMC2):​c.338C>T​(p.Ala113Val) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMC2 NM_080751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148
• Publications: 0 publications found

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]

ENSG00000298229 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06177774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080751.3. 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
	TMC2	NM_080751.3	MANE Select	c.338C>T	p.Ala113Val	missense	Exon 3 of 20	NP_542789.2	Q8TDI7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC2	ENST00000358864.2	TSL:1 MANE Select	c.338C>T	p.Ala113Val	missense	Exon 3 of 20	ENSP00000351732.1	Q8TDI7-1
	TMC2	ENST00000644205.1		n.497C>T		non_coding_transcript_exon	Exon 1 of 15
	ENSG00000298229	ENST00000753996.1		n.60+429G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.15
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.050
Sift	Benign	0.036	D
Sift4G	Benign	0.26	T
Polyphen		0.0040	B
Vest4		0.037
MutPred		0.18		Loss of glycosylation at P114 (P = 0.1051)
MVP		0.15
MPC		0.13
ClinPred		0.094	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.13
Mutation Taster		=98/2	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

hg19: chr20-2539357; COSMIC: COSV104664936;