rs139835231

Positions:

• chr1-40837737-C-A
• chr1-40837737-C-G
• chr1-40837737-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004700.4(KCNQ4):​c.1818C>A​(p.Asp606Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164

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]

KCNQ4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05273196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1818C>A	p.Asp606Glu	missense_variant	13/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1818C>A	p.Asp606Glu	missense_variant	13/14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1656C>A	p.Asp552Glu	missense_variant	12/13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.1398C>A	p.Asp466Glu	missense_variant	12/13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.1137C>A		non_coding_transcript_exon_variant	10/11	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	2.0
DANN	Benign	0.41
DEOGEN2	Uncertain	0.51	D;D;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.56	.;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.040	.;N;N
REVEL	Benign	0.28
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.86	.;T;T
Polyphen		0.036	B;B;B
Vest4		0.16, 0.17
MutPred		0.41		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;
MVP		0.55
MPC		0.92
ClinPred		0.13	T
GERP RS		-2.7
Varity_R		0.047
gMVP		0.13

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: rs139835231; hg19: chr1-41303409;