1-40835347-T-C

Variant names:

• chr1-40835347-T-C
• rs729589
• NM_004700.4:c.1745+249T>C

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.1745+249T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,196 control chromosomes in the GnomAD database, including 17,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.45 (17299 hom., cov: 33)
• Consequence: KCNQ4 NM_004700.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.16
• Publications: 3 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, PanelApp Australia
• 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 (BayesDel_noAF=-0.97).
• BP6: Variant 1-40835347-T-C is Benign according to our data. Variant chr1-40835347-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 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.1745+249T>C		intron	N/A	NP_004691.2
	KCNQ4	NM_172163.3		c.1583+249T>C		intron	N/A	NP_751895.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ4	ENST00000347132.10	TSL:1 MANE Select	c.1745+249T>C		intron	N/A	ENSP00000262916.6
	KCNQ4	ENST00000967337.1		c.1685+249T>C		intron	N/A	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.1628+249T>C		intron	N/A	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 69020 AN: 152078 Hom.: 17299 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.471

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.454 AC: 69026 AN: 152196 Hom.: 17299 Cov.: 33 AF XY: 0.455 AC XY: 33877 AN XY: 74420

African (AFR) AF: 0.243 AC: 10104 AN: 41530

American (AMR) AF: 0.427 AC: 6531 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1839 AN: 3468

East Asian (EAS) AF: 0.779 AC: 4030 AN: 5174

South Asian (SAS) AF: 0.557 AC: 2685 AN: 4818

European-Finnish (FIN) AF: 0.527 AC: 5592 AN: 10608

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36593 AN: 68000

Other (OTH) AF: 0.478 AC: 1007 AN: 2108

Alfa AF: 0.486 Hom.: 3122

Bravo AF: 0.436

Asia WGS AF: 0.645 AC: 2241 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.011
DANN	Benign	0.48
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs729589; hg19: chr1-41301019;