rs2072413

Variant names:

• chr7-150950881-C-T
• rs2072413
• NM_000238.4:c.2145+40G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000238.4(KCNH2):​c.2145+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,599,804 control chromosomes in the GnomAD database, including 56,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6075 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50797 hom.)
• Consequence: KCNH2 NM_000238.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-150950881-C-T is Benign according to our data. Variant chr7-150950881-C-T is described in ClinVar as Benign. ClinVar VariationId is 671018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2145+40G>A		intron_variant	Intron 8 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2145+40G>A		intron_variant	Intron 8 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 41996 AN: 151884 Hom.: 6052 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.236 AC: 58838 AN: 249092 AF XY: 0.240

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.261 AC: 377793 AN: 1447802 Hom.: 50797 Cov.: 30 AF XY: 0.261 AC XY: 187790 AN XY: 720862

African (AFR) AF: 0.354 AC: 11745 AN: 33142

American (AMR) AF: 0.152 AC: 6785 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5915 AN: 26032

East Asian (EAS) AF: 0.110 AC: 4357 AN: 39630

South Asian (SAS) AF: 0.237 AC: 20395 AN: 85890

European-Finnish (FIN) AF: 0.237 AC: 12607 AN: 53168

Middle Eastern (MID) AF: 0.282 AC: 1421 AN: 5032

European-Non Finnish (NFE) AF: 0.272 AC: 298799 AN: 1100454

Other (OTH) AF: 0.263 AC: 15769 AN: 59852

GnomAD4 genome AF: 0.277 AC: 42055 AN: 152002 Hom.: 6075 Cov.: 33 AF XY: 0.273 AC XY: 20283 AN XY: 74292

African (AFR) AF: 0.346 AC: 14355 AN: 41436

American (AMR) AF: 0.217 AC: 3320 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 789 AN: 3466

East Asian (EAS) AF: 0.127 AC: 653 AN: 5148

South Asian (SAS) AF: 0.250 AC: 1209 AN: 4828

European-Finnish (FIN) AF: 0.225 AC: 2385 AN: 10586

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18425 AN: 67944

Other (OTH) AF: 0.275 AC: 579 AN: 2108

Alfa AF: 0.284 Hom.: 2665

Bravo AF: 0.277

Asia WGS AF: 0.225 AC: 784 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.88
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
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: rs2072413; hg19: chr7-150647969; COSMIC: COSV51177184;