chr1-40831156-T-G

Variant names:

• chr1-40831156-T-G
• rs34287852
• NM_004700.4:c.1365T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004700.4(KCNQ4):​c.1365T>G​(p.His455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,609,926 control chromosomes in the GnomAD database, including 40,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2747 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37862 hom.)
• Consequence: KCNQ4 NM_004700.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0130
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013206303).
• BP6: Variant 1-40831156-T-G is Benign according to our data. Variant chr1-40831156-T-G is described in ClinVar as Benign. ClinVar VariationId is 45101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	NM_004700.4	MANE Select	c.1365T>G	p.His455Gln	missense	Exon 10 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.1203T>G	p.His401Gln	missense	Exon 9 of 13	NP_751895.1	P56696-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.1365T>G	p.His455Gln	missense	Exon 10 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.1305T>G	p.His435Gln	missense	Exon 10 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.1248T>G	p.His416Gln	missense	Exon 10 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25408 AN: 151972 Hom.: 2746 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0601

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.176 AC: 42379 AN: 240294 AF XY: 0.181

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.0987

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.0639

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.221 AC: 322064 AN: 1457836 Hom.: 37862 Cov.: 37 AF XY: 0.219 AC XY: 158757 AN XY: 724852

African (AFR) AF: 0.0337 AC: 1127 AN: 33436

American (AMR) AF: 0.106 AC: 4704 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4342 AN: 26050

East Asian (EAS) AF: 0.0492 AC: 1949 AN: 39604

South Asian (SAS) AF: 0.129 AC: 11043 AN: 85704

European-Finnish (FIN) AF: 0.261 AC: 13724 AN: 52636

Middle Eastern (MID) AF: 0.183 AC: 1054 AN: 5764

European-Non Finnish (NFE) AF: 0.245 AC: 271787 AN: 1110048

Other (OTH) AF: 0.205 AC: 12334 AN: 60218

GnomAD4 genome AF: 0.167 AC: 25413 AN: 152090 Hom.: 2747 Cov.: 32 AF XY: 0.165 AC XY: 12253 AN XY: 74344

African (AFR) AF: 0.0430 AC: 1785 AN: 41532

American (AMR) AF: 0.140 AC: 2133 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 581 AN: 3470

East Asian (EAS) AF: 0.0598 AC: 309 AN: 5164

South Asian (SAS) AF: 0.128 AC: 617 AN: 4824

European-Finnish (FIN) AF: 0.264 AC: 2785 AN: 10556

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16619 AN: 67956

Other (OTH) AF: 0.169 AC: 357 AN: 2112

Alfa AF: 0.215 Hom.: 5376

Bravo AF: 0.153

TwinsUK AF: 0.255 AC: 947

ALSPAC AF: 0.253 AC: 976

ESP6500AA AF: 0.0488 AC: 215

ESP6500EA AF: 0.240 AC: 2062

ExAC AF: 0.173 AC: 20979

Asia WGS AF: 0.111 AC: 388 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal dominant nonsyndromic hearing loss 2A (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.013
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.29
Sift	Benign	0.54	T
Sift4G	Benign	0.40	T
Polyphen		0.022	B
Vest4		0.099
MutPred		0.20		Gain of MoRF binding (P = 0.0966)
MPC		0.13
ClinPred		0.0016	T
GERP RS		2.0
Varity_R		0.057
gMVP		0.25
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34287852; hg19: chr1-41296828; COSMIC: COSV61273114;