rs2589614

Variant names:

• chr9-72694930-T-C
• rs2589614
• NM_138691.3:c.236+216T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-72694930-T-C
• chr9-72694930-T-A
• chr9-72694930-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138691.3(TMC1):​c.236+216T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,942 control chromosomes in the GnomAD database, including 21,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (21258 hom., cov: 32)
• Consequence: TMC1 NM_138691.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 3 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-72694930-T-C is Benign according to our data. Variant chr9-72694930-T-C is described in ClinVar as Benign. ClinVar VariationId is 1276753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. 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
	TMC1	NM_138691.3	MANE Select	c.236+216T>C		intron	N/A	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.236+216T>C		intron	N/A	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.236+216T>C		intron	N/A	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.236+216T>C		intron	N/A	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77753 AN: 151824 Hom.: 21231 Cov.: 32

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.512 AC: 77832 AN: 151942 Hom.: 21258 Cov.: 32 AF XY: 0.510 AC XY: 37845 AN XY: 74264

African (AFR) AF: 0.726 AC: 30066 AN: 41428

American (AMR) AF: 0.462 AC: 7040 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3468

East Asian (EAS) AF: 0.430 AC: 2218 AN: 5162

South Asian (SAS) AF: 0.444 AC: 2139 AN: 4822

European-Finnish (FIN) AF: 0.422 AC: 4450 AN: 10556

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28647 AN: 67938

Other (OTH) AF: 0.513 AC: 1084 AN: 2112

Alfa AF: 0.467 Hom.: 2068

Bravo AF: 0.525

Asia WGS AF: 0.458 AC: 1583 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.81
PhyloP100		-1.0
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: rs2589614; hg19: chr9-75309846; COSMIC: COSV52771171;