rs749565877

Positions:

• chr1-40838441-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004700.4(KCNQ4):​c.2006A>G​(p.His669Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (1 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.25

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18126044).
• BP6: Variant 1-40838441-A-G is Benign according to our data. Variant chr1-40838441-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228775.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000903 (132/1461788) while in subpopulation SAS AF= 0.00104 (90/86256). AF 95% confidence interval is 0.000869. There are 1 homozygotes in gnomad4_exome. There are 86 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ4	NM_004700.4	c.2006A>G	p.His669Arg	missense_variant	14/14	ENST00000347132.10
KCNQ4	NM_172163.3	c.1844A>G	p.His615Arg	missense_variant	13/13
KCNQ4	XM_017002792.2	c.989A>G	p.His330Arg	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ4	ENST00000347132.10	c.2006A>G	p.His669Arg	missense_variant	14/14	1	NM_004700.4	P2
KCNQ4	ENST00000509682.6	c.1844A>G	p.His615Arg	missense_variant	13/13	5		A1
KCNQ4	ENST00000443478.3	c.1589A>G	p.His530Arg	missense_variant	13/13	5
KCNQ4	ENST00000506017.1	n.1325A>G		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251240 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135816

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: 0.000947

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461788 Hom.: 1 Cov.: 31 AF XY: 0.000118 AC XY: 86 AN XY: 727212

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: 0.00104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000697 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	KCNQ4: BS1 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.His669Arg var iant in KCNQ4 has not been previously reported in individuals with hearing loss, but has been identified in 0.1% (18/16512) of South Asian chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs749565 877). Although this variant has been seen in the general population, its frequen cy is not high enough to rule out a pathogenic role. Computational prediction to ols and conservation analysis suggest that the p.His669Arg variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. In summary, while the clinical significance of the p.His669Arg varian t is uncertain, its frequency in the general population and computational analys es suggest that it is more likely to be benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

The c.2006A>G (p.H669R) alteration is located in exon 14 (coding exon 14) of the KCNQ4 gene. This alteration results from a A to G substitution at nucleotide position 2006, causing the histidine (H) at amino acid position 669 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
Polyphen		0.85	P;P;B
Vest4		0.37, 0.52
MutPred		0.28		Gain of phosphorylation at S666 (P = 0.0974);Gain of phosphorylation at S666 (P = 0.0974);.;
MVP		0.74
MPC		1.9
ClinPred		0.23	T
GERP RS		4.9
Varity_R		0.70
gMVP		0.55

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: rs749565877; hg19: chr1-41304113;