rs1190669660

Variant names:

• chr1-40784120-C-T
• rs1190669660
• NM_004700.4:c.27C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40784120-C-T
• chr1-40784120-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_004700.4(KCNQ4):​c.27C>T​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 146,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ4 NM_004700.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.40
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-40784120-C-T is Benign according to our data. Variant chr1-40784120-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1553452.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.4 with no splicing effect.

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.27C>T	p.Leu9Leu	synonymous	Exon 1 of 14	NP_004691.2
	KCNQ4	NM_172163.3		c.27C>T	p.Leu9Leu	synonymous	Exon 1 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.27C>T	p.Leu9Leu	synonymous	Exon 1 of 14	ENSP00000262916.6	P56696-1
	KCNQ4	ENST00000967337.1		c.27C>T	p.Leu9Leu	synonymous	Exon 1 of 14	ENSP00000637396.1
	KCNQ4	ENST00000967338.1		c.27C>T	p.Leu9Leu	synonymous	Exon 1 of 14	ENSP00000637397.1

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146604 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 1 AN: 695448 Hom.: 0 Cov.: 9 AF XY: 0.00000302 AC XY: 1 AN XY: 331118

African (AFR) AF: 0.00 AC: 0 AN: 13084

American (AMR) AF: 0.00 AC: 0 AN: 2106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4868

East Asian (EAS) AF: 0.00 AC: 0 AN: 4124

South Asian (SAS) AF: 0.00 AC: 0 AN: 15856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1500

European-Non Finnish (NFE) AF: 0.00000159 AC: 1 AN: 627764

Other (OTH) AF: 0.00 AC: 0 AN: 23224

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146604 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71280

African (AFR) AF: 0.00 AC: 0 AN: 40870

American (AMR) AF: 0.00 AC: 0 AN: 14776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65926

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.98
PhyloP100		2.4
PromoterAI		-0.054	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1190669660; hg19: chr1-41249792;