rs757779139

Variant names:

• chr20-2558636-G-C
• rs757779139
• NM_080751.3:c.263G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-2558636-G-C
• chr20-2558636-G-T
• chr20-2558636-G-A

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.263G>C​(p.Arg88Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,417,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMC2 NM_080751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.766
• 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=0.046910137).

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.263G>C	p.Arg88Pro	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.263G>C	p.Arg88Pro	missense	Exon 3 of 20	ENSP00000351732.1	Q8TDI7-1
	TMC2	ENST00000644205.1		n.422G>C		non_coding_transcript_exon	Exon 1 of 15
	ENSG00000298229	ENST00000753996.1		n.60+504C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 180686 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000282 AC: 4 AN: 1417546 Hom.: 0 Cov.: 29 AF XY: 0.00000285 AC XY: 2 AN XY: 700672

African (AFR) AF: 0.00 AC: 0 AN: 32526

American (AMR) AF: 0.00 AC: 0 AN: 37110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37632

South Asian (SAS) AF: 0.00 AC: 0 AN: 80706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089204

Other (OTH) AF: 0.00 AC: 0 AN: 58806

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000835 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.088
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.45
DANN	Benign	0.58
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.77
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.010
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.082
MVP		0.030
MPC		0.18
ClinPred		0.050	T
GERP RS		-5.6
Varity_R		0.10
gMVP		0.12
Mutation Taster		=89/11	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

dbSNP: rs757779139; hg19: chr20-2539282;