chr1-40824154-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004700.4(KCNQ4):​c.1188C>T​(p.Pro396Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,568,878 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

KCNQ4
NM_004700.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.29
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 Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 1-40824154-C-T is Benign according to our data. Variant chr1-40824154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40824154-C-T is described in Lovd as [Likely_benign]. Variant chr1-40824154-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.29 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00212 (323/152358) while in subpopulation AMR AF= 0.00359 (55/15310). AF 95% confidence interval is 0.00293. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 323 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ4NM_004700.4 linkc.1188C>T p.Pro396Pro synonymous_variant Exon 9 of 14 ENST00000347132.10 NP_004691.2 P56696-1B3KQH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ4ENST00000347132.10 linkc.1188C>T p.Pro396Pro synonymous_variant Exon 9 of 14 1 NM_004700.4 ENSP00000262916.6 P56696-1
KCNQ4ENST00000509682.6 linkc.1130+1752C>T intron_variant Intron 8 of 12 5 ENSP00000423756.2 P56696-2
KCNQ4ENST00000443478.3 linkc.815+1752C>T intron_variant Intron 7 of 12 5 ENSP00000406735.3 H0Y6N7
KCNQ4ENST00000506017.1 linkn.507C>T non_coding_transcript_exon_variant Exon 6 of 11 2

Frequencies

GnomAD3 genomes
AF:
0.00212
AC:
323
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00360
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000847
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00328
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00186
AC:
321
AN:
172394
Hom.:
1
AF XY:
0.00198
AC XY:
186
AN XY:
93714
show subpopulations
Gnomad AFR exome
AF:
0.000221
Gnomad AMR exome
AF:
0.00146
Gnomad ASJ exome
AF:
0.00103
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000247
Gnomad FIN exome
AF:
0.000550
Gnomad NFE exome
AF:
0.00357
Gnomad OTH exome
AF:
0.00171
GnomAD4 exome
AF:
0.00327
AC:
4630
AN:
1416520
Hom.:
12
Cov.:
33
AF XY:
0.00308
AC XY:
2157
AN XY:
700704
show subpopulations
Gnomad4 AFR exome
AF:
0.000341
Gnomad4 AMR exome
AF:
0.00169
Gnomad4 ASJ exome
AF:
0.00118
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000198
Gnomad4 FIN exome
AF:
0.000833
Gnomad4 NFE exome
AF:
0.00394
Gnomad4 OTH exome
AF:
0.00285
GnomAD4 genome
AF:
0.00212
AC:
323
AN:
152358
Hom.:
0
Cov.:
33
AF XY:
0.00192
AC XY:
143
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000553
Gnomad4 AMR
AF:
0.00359
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000847
Gnomad4 NFE
AF:
0.00328
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00286
Hom.:
0
Bravo
AF:
0.00269

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KCNQ4: BP4, BS2 -

Dec 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 09, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 26, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10571947) -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:2
Apr 30, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Pro396Pro in exon 09 of KCNQ4: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.7% (55/8302) of E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs189541861). -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 2A Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

KCNQ4-related disorder Benign:1
Jan 24, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
14
DANN
Benign
0.91

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

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

Other links and lift over

dbSNP: rs189541861; hg19: chr1-41289826; API