rs1347676173

Variant names:

• chr1-40784146-C-A
• rs1347676173
• NM_004700.4:c.53C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-40784146-C-A
• chr1-40784146-C-G
• chr1-40784146-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004700.4(KCNQ4):​c.53C>A​(p.Ala18Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 885,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. A18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.745

Genes affected

KCNQ4 (HGNC:6298): (potassium voltage-gated channel subfamily Q member 4) The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15200615).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.53C>A	p.Ala18Asp	missense_variant	Exon 1 of 14	ENST00000347132.10	NP_004691.2
KCNQ4	NM_172163.3	c.53C>A	p.Ala18Asp	missense_variant	Exon 1 of 13		NP_751895.1
KCNQ4	XM_047434057.1	c.53C>A	p.Ala18Asp	missense_variant	Exon 1 of 13		XP_047290013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.53C>A	p.Ala18Asp	missense_variant	Exon 1 of 14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.53C>A	p.Ala18Asp	missense_variant	Exon 1 of 13	5		ENSP00000423756.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000904 AC: 8 AN: 885416 Hom.: 0 Cov.: 14 AF XY: 0.0000117 AC XY: 5 AN XY: 425634

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000368

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000898

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.43	.;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	-1.4	N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.60	.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.081	.;T;T
Sift4G	Benign	0.64	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.25, 0.16
MutPred		0.14		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.49
MPC		1.6
ClinPred		0.13	T
GERP RS		1.7
Varity_R		0.15
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs1347676173; hg19: chr1-41249818;