rs1031478932

Variant names:

• chr7-150955403-G-A
• rs1031478932
• ENST00000330883.9:c.101C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The ENST00000262186.10(KCNH2):​c.1128+1888C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,406,880 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 (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNH2 ENST00000262186.10 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20949075).
• BP6: Variant 7-150955403-G-A is Benign according to our data. Variant chr7-150955403-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456881.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262186.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1128+1888C>T		intron	N/A	NP_000229.1
	KCNH2	NM_172057.3		c.101C>T	p.Ala34Val	missense	Exon 1 of 11	NP_742054.1
	KCNH2	NM_001204798.2		c.101C>T	p.Ala34Val	missense	Exon 1 of 5	NP_001191727.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000330883.9	TSL:1	c.101C>T	p.Ala34Val	missense	Exon 1 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.419C>T		non_coding_transcript_exon	Exon 1 of 5
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1128+1888C>T		intron	N/A	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1406880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695054

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31920

American (AMR) AF: 0.0000268 AC: 1 AN: 37378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 36332

South Asian (SAS) AF: 0.00 AC: 0 AN: 79692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084098

Other (OTH) AF: 0.00 AC: 0 AN: 58250

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.093
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.61	D
PhyloP100		2.0
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.38
Sift	Benign	0.044	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0	B
Vest4		0.096
MutPred		0.29		Gain of MoRF binding (P = 0.1332)
MVP		0.91
ClinPred		0.38	T
GERP RS		5.0
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1031478932; hg19: chr7-150652491;