rs146883958

chr14-62950404-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_139318.5(KCNH5):c.1098A>G(p.Ile366Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,944 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. I366V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: KCNH5 NM_139318.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.956

Genes affected

KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNH5
• BP4: Computational evidence support a benign effect (MetaRNN=0.040032953).
• BP6: Variant 14-62950404-T-C is Benign according to our data. Variant chr14-62950404-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 416115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-62950404-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH5	NM_139318.5	c.1098A>G	p.Ile366Met	missense_variant	7/11	ENST00000322893.12
KCNH5	NM_172375.3	c.1098A>G	p.Ile366Met	missense_variant	7/10
KCNH5	XM_047431275.1	c.1098A>G	p.Ile366Met	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH5	ENST00000322893.12	c.1098A>G	p.Ile366Met	missense_variant	7/11	1	NM_139318.5	P1
KCNH5	ENST00000420622.6	c.1098A>G	p.Ile366Met	missense_variant	7/10	1
KCNH5	ENST00000394964.3	n.1263A>G		non_coding_transcript_exon_variant	7/7	1
KCNH5	ENST00000394968.2	c.924A>G	p.Ile308Met	missense_variant	7/11	2

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00114 AC: 285 AN: 250870 Hom.: 0 AF XY: 0.00106 AC XY: 144 AN XY: 135562

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00108 AC: 1586 AN: 1461802 Hom.: 2 Cov.: 32 AF XY: 0.00108 AC XY: 782 AN XY: 727202

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.000699 AC XY: 52 AN XY: 74380

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000929

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

KCNH5-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	D;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.049	D;T;T
Polyphen		0.85	P;B;P
Vest4		0.86
MVP		0.94
MPC		1.8
ClinPred		0.058	T
GERP RS		-6.6
Varity_R		0.45
gMVP		0.70

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

Other links and lift over

dbSNP: rs146883958; hg19: chr14-63417122; COSMIC: COSV105235765;