rs79489451

Positions:

• chr14-62950126-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000322893.12(KCNH5):​c.1369+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,270 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: KCNH5 ENST00000322893.12 splice_region, intron
• Scores: Splicing: ADA: 0.01885
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.66

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 14-62950126-T-C is Benign according to our data. Variant chr14-62950126-T-C is described in ClinVar as [Benign]. Clinvar id is 416118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00762 (1160/152242) while in subpopulation AFR AF= 0.0265 (1102/41548). AF 95% confidence interval is 0.0252. There are 11 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1160 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH5	NM_139318.5	c.1369+7A>G		splice_region_variant, intron_variant		ENST00000322893.12	NP_647479.2
KCNH5	NM_172375.3	c.1369+7A>G		splice_region_variant, intron_variant			NP_758963.1
KCNH5	XM_047431275.1	c.1369+7A>G		splice_region_variant, intron_variant			XP_047287231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH5	ENST00000322893.12	c.1369+7A>G		splice_region_variant, intron_variant		1	NM_139318.5	ENSP00000321427	P1
KCNH5	ENST00000420622.6	c.1369+7A>G		splice_region_variant, intron_variant		1		ENSP00000395439
KCNH5	ENST00000394964.3	n.1541A>G		non_coding_transcript_exon_variant	7/7	1
KCNH5	ENST00000394968.2	c.1195+7A>G		splice_region_variant, intron_variant		2		ENSP00000378419

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1158 AN: 152124 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00205 AC: 511 AN: 249754 Hom.: 7 AF XY: 0.00169 AC XY: 228 AN XY: 135038

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000756 AC: 1104 AN: 1460028 Hom.: 10 Cov.: 30 AF XY: 0.000651 AC XY: 473 AN XY: 726330

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152242 Hom.: 11 Cov.: 31 AF XY: 0.00730 AC XY: 543 AN XY: 74432

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00399 Hom.: 1

Bravo AF: 0.00869

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2020

- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

KCNH5-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as 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	-0.37
CADD	Benign	16
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.019
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.080		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: rs79489451; hg19: chr14-63416844;