chr1-40819470-A-G

Position:

chr1-40819470-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_004700.4(KCNQ4):c.832A>G(p.Thr278Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000062 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KCNQ4
NM_004700.4 missense, splice_region

Scores

Splicing: ADA: 0.3557

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46

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]

KCNQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a intramembrane_region Pore-forming; Name=Segment H5 (size 21) in uniprot entity KCNQ4_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_004700.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ4	NM_004700.4 linkuse as main transcript	c.832A>G	p.Thr278Ala	missense_variant, splice_region_variant	5/14	ENST00000347132.10	NP_004691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ4	ENST00000347132.10 linkuse as main transcript	c.832A>G	p.Thr278Ala	missense_variant, splice_region_variant	5/14	1	NM_004700.4	ENSP00000262916	P2	P56696-1
KCNQ4	ENST00000509682.6 linkuse as main transcript	c.832A>G	p.Thr278Ala	missense_variant, splice_region_variant	5/13	5		ENSP00000423756	A1	P56696-2
KCNQ4	ENST00000443478.3 linkuse as main transcript	c.520A>G	p.Thr174Ala	missense_variant, splice_region_variant	4/13	5		ENSP00000406735
KCNQ4	ENST00000506017.1 linkuse as main transcript	n.151A>G		splice_region_variant, non_coding_transcript_exon_variant	2/11	2

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251390

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000410

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74032

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000140

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 11, 2017

The p.Thr278Ala variant in KCNQ4 has not been previously reported in individuals with hearing loss, but has been identified in 1/33578 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP r s763326539). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact to the protein. This variant is located in the last three bases of t he exon, which is part of the 5? splice region. Computational tools do not sugge st an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr278Ala variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.94

L;L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

.;D;D

REVEL

Pathogenic

0.79

Sift

Benign

0.034

.;D;D

Sift4G

Benign

0.39

.;T;T

Polyphen

1.0

D;D;P

Vest4

0.72, 0.69

MutPred

0.51

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.94

MPC

2.1

ClinPred

0.96

GERP RS

5.1

Varity_R

0.65

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.36

dbscSNV1_RF

Benign

0.42

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over