NM_000238.4:c.308-5506G>A

Variant names:

• chr7-150965242-C-T
• rs2968857
• NM_000238.4:c.308-5506G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000238.4(KCNH2):​c.308-5506G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 151,710 control chromosomes in the GnomAD database, including 38,738 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (38738 hom., cov: 28)
• Consequence: KCNH2 NM_000238.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.258
• Publications: 6 publications found

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.308-5506G>A		intron_variant	Intron 2 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.308-5506G>A		intron_variant	Intron 2 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106713 AN: 151592 Hom.: 38675 Cov.: 28

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.679

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.704 AC: 106841 AN: 151710 Hom.: 38738 Cov.: 28 AF XY: 0.706 AC XY: 52323 AN XY: 74092

African (AFR) AF: 0.876 AC: 36251 AN: 41360

American (AMR) AF: 0.667 AC: 10179 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2121 AN: 3468

East Asian (EAS) AF: 0.883 AC: 4551 AN: 5152

South Asian (SAS) AF: 0.671 AC: 3200 AN: 4766

European-Finnish (FIN) AF: 0.638 AC: 6712 AN: 10526

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41639 AN: 67876

Other (OTH) AF: 0.684 AC: 1440 AN: 2106

Alfa AF: 0.634 Hom.: 17738

Bravo AF: 0.715

Asia WGS AF: 0.763 AC: 2653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.70
DANN	Benign	0.78
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2968857; hg19: chr7-150662330;