NM_000238.4:c.1842G>C

Variant names:

• chr7-150951551-C-G
• rs746863761
• NM_000238.4:c.1842G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000238.4(KCNH2):​c.1842G>C​(p.Ala614Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A614A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.17
• Publications: 0 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-150951551-C-G is Benign according to our data. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951551-C-G is described in CliVar as Likely_benign. Clinvar id is 2897483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.17 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1842G>C	p.Ala614Ala	synonymous_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1842G>C	p.Ala614Ala	synonymous_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Feb 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 28, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.17
DANN	Benign	0.44
PhyloP100		-4.2

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs746863761; hg19: chr7-150648639;