chr1-210683289-C-A

Position:

chr1-210683289-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_172362.3(KCNH1):c.2962G>T(p.Ala988Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,726 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A988G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

KCNH1
NM_172362.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KCNH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH1. . Gene score misZ 3.8156 (greater than the threshold 3.09). Trascript score misZ 5.0674 (greater than threshold 3.09). GenCC has associacion of gene with KCNH1 associated disorder, Zimmermann-Laband syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.061391562).

BP6

Variant 1-210683289-C-A is Benign according to our data. Variant chr1-210683289-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 710791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH1	NM_172362.3 linkuse as main transcript	c.2962G>T	p.Ala988Ser	missense_variant	11/11	ENST00000271751.10	NP_758872.1	O95259-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10 linkuse as main transcript	c.2962G>T	p.Ala988Ser	missense_variant	11/11	2	NM_172362.3	ENSP00000271751.4		O95259-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000156

AC:

AN:

250628

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000820

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1460690

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000952

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	- -

KCNH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

T;.;T;T

M_CAP

Benign

0.083

MetaRNN

Benign

0.061

T;T;T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.060

N;.;.;.

MutationTaster

Benign

0.56

D;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.29

N;.;.;.

REVEL

Uncertain

0.46

Sift

Benign

0.073

T;.;.;.

Sift4G

Benign

0.29

T;.;.;.

Polyphen

0.0010

B;.;.;.

Vest4

0.28

MVP

0.84

MPC

0.15

ClinPred

0.044

GERP RS

5.1

Varity_R

0.15

gMVP

0.16

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.

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