rs1553168273

Positions:

• chr1-40831197-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004700.4(KCNQ4):​c.1406A>G​(p.Gln469Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24952227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4	c.1406A>G	p.Gln469Arg	missense_variant	10/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10	c.1406A>G	p.Gln469Arg	missense_variant	10/14	1	NM_004700.4	ENSP00000262916.6
KCNQ4	ENST00000509682.6	c.1244A>G	p.Gln415Arg	missense_variant	9/13	5		ENSP00000423756.2
KCNQ4	ENST00000443478.3	c.986A>G	p.Gln329Arg	missense_variant	9/13	5		ENSP00000406735.3
KCNQ4	ENST00000506017.1	n.725A>G		non_coding_transcript_exon_variant	7/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 14, 2017

The p.Gln469Arg variant in KCNQ4 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analyses suggest that this variant may not impact the protein , though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gln469Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.49	.;T;T
Sift4G	Benign	0.52	.;T;T
Polyphen		0.19	B;B;B
Vest4		0.22, 0.21
MutPred		0.36		Gain of catalytic residue at Q469 (P = 0.0241);Gain of catalytic residue at Q469 (P = 0.0241);.;
MVP		0.78
MPC		0.14
ClinPred		0.55	D
GERP RS		5.1
Varity_R		0.13
gMVP		0.26

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: rs1553168273; hg19: chr1-41296869;