rs2278669

Variant names:

• chr9-72597302-A-G
• rs2278669
• NM_138691.3:c.-305-19066A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138691.3(TMC1):​c.-305-19066A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 152,086 control chromosomes in the GnomAD database, including 18,529 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (18529 hom., cov: 33)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13
• Publications: 1 publications found

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

TMC1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.-305-19066A>G		intron_variant	Intron 2 of 23	ENST00000297784.10	NP_619636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.-305-19066A>G		intron_variant	Intron 2 of 23	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74619 AN: 151968 Hom.: 18512 Cov.: 33

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.491 AC: 74688 AN: 152086 Hom.: 18529 Cov.: 33 AF XY: 0.490 AC XY: 36420 AN XY: 74328

African (AFR) AF: 0.566 AC: 23486 AN: 41494

American (AMR) AF: 0.481 AC: 7350 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1674 AN: 3472

East Asian (EAS) AF: 0.432 AC: 2228 AN: 5160

South Asian (SAS) AF: 0.421 AC: 2027 AN: 4820

European-Finnish (FIN) AF: 0.482 AC: 5086 AN: 10554

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31290 AN: 67988

Other (OTH) AF: 0.493 AC: 1041 AN: 2110

Alfa AF: 0.489 Hom.: 2352

Bravo AF: 0.496

Asia WGS AF: 0.446 AC: 1549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0090
DANN	Benign	0.27
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2278669; hg19: chr9-75212218; COSMIC: COSV52770467;