rs772394226

Variant names:

• chr16-19440706-C-A
• rs772394226
• NM_001261841.2:c.668C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-19440706-C-A
• chr16-19440706-C-G
• chr16-19440706-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001261841.2(TMC5):​c.668C>A​(p.Pro223Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P223L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.33

Genes affected

TMC5 (HGNC:22999): (transmembrane channel like 5) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC5	NM_001261841.2	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 22	ENST00000542583.7	NP_001248770.1
TMC5	NM_001105248.1	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 22		NP_001098718.1
TMC5	NM_001308161.1	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 21		NP_001295090.1
TMC5	NM_001105249.1	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 21		NP_001098719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC5	ENST00000542583.7	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 22	2	NM_001261841.2	ENSP00000446274.2
TMC5	ENST00000381414.8	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 21	1		ENSP00000370822.4
TMC5	ENST00000396229.6	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 22	5		ENSP00000379531.2
TMC5	ENST00000541464.5	c.668C>A	p.Pro223Gln	missense_variant	Exon 3 of 21	2		ENSP00000441227.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134978

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	.;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;T;.
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	.;M;M;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.50
MutPred		0.39		Loss of glycosylation at P223 (P = 0.0907);Loss of glycosylation at P223 (P = 0.0907);Loss of glycosylation at P223 (P = 0.0907);Loss of glycosylation at P223 (P = 0.0907);
MVP		0.71
MPC		0.63
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.091
gMVP		0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs772394226; hg19: chr16-19452028;