rs745885744

Variant names:

• chr7-150974925-G-A
• rs745885744
• NM_000238.4:c.93C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150974925-G-A
• chr7-150974925-G-C
• chr7-150974925-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Very_Strong BP7 BS2_Supporting

The NM_000238.4(KCNH2):​c.93C>T​(p.Ile31Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I31I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KCNH2 NM_000238.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.834
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-150974925-G-A is Benign according to our data. Variant chr7-150974925-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.834 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.93C>T	p.Ile31Ile	synonymous_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.93C>T	p.Ile31Ile	synonymous_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000713710.1	c.93C>T	p.Ile31Ile	synonymous_variant	Exon 2 of 15			ENSP00000519013.1
KCNH2	ENST00000532957.5	n.316C>T		non_coding_transcript_exon_variant	Exon 2 of 9	2
KCNH2	ENST00000713700.1	n.51C>T		non_coding_transcript_exon_variant	Exon 2 of 9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237524 AF XY: 0.00000772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000940

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1454672 Hom.: 0 Cov.: 34 AF XY: 0.00000553 AC XY: 4 AN XY: 723332

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109760

Other (OTH) AF: 0.00 AC: 0 AN: 60154

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

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 24, 2020

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	-0.33
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism

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: rs745885744; hg19: chr7-150672013;