1-40819415-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_004700.4(KCNQ4):ā€‹c.777T>Gā€‹(p.Ala259Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,726 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 Lovd as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.41
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
BP6
Variant 1-40819415-T-G is Benign according to our data. Variant chr1-40819415-T-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-4.41 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ4NM_004700.4 linkc.777T>G p.Ala259Ala synonymous_variant 5/14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.777T>G p.Ala259Ala synonymous_variant 5/141 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.777T>G p.Ala259Ala synonymous_variant 5/135 ENSP00000423756.2 P56696-2
KCNQ4ENST00000443478.3 linkc.462T>G p.Ala154Ala synonymous_variant 4/135 ENSP00000406735.3 H0Y6N7
KCNQ4ENST00000506017.1 linkn.96T>G non_coding_transcript_exon_variant 2/112

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251388
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461726
Hom.:
0
Cov.:
56
AF XY:
0.00000138
AC XY:
1
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
CADD
Benign
3.5
DANN
Benign
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4660468; hg19: chr1-41285087; API