7-150948437-G-C

Variant names:

• chr7-150948437-G-C
• rs372023163
• NM_000238.4:c.2692+7C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000238.4(KCNH2):​c.2692+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003167
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.817
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-150948437-G-C is Benign according to our data. Variant chr7-150948437-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 456915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.2692+7C>G		splice_region_variant, intron_variant	Intron 11 of 14	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.2692+7C>G		splice_region_variant, intron_variant	Intron 11 of 14	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 1490 AN: 37994 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.0361

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00536

Gnomad SAS AF: 0.0144

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0449

Gnomad OTH AF: 0.0305

GnomAD2 exomes AF: 0.0167 AC: 2514 AN: 150676 AF XY: 0.0150

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.0403

Gnomad FIN exome AF: 0.00519

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0367

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0156 AC: 7734 AN: 496546 Hom.: 0 Cov.: 16 AF XY: 0.0162 AC XY: 4211 AN XY: 260528

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

African (AFR) AF: 0.0336 AC: 223 AN: 6638

American (AMR) AF: 0.0333 AC: 709 AN: 21308

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 199 AN: 11540

East Asian (EAS) AF: 0.0392 AC: 391 AN: 9964

South Asian (SAS) AF: 0.0361 AC: 1483 AN: 41030

European-Finnish (FIN) AF: 0.0167 AC: 324 AN: 19454

Middle Eastern (MID) AF: 0.00703 AC: 21 AN: 2986

European-Non Finnish (NFE) AF: 0.0111 AC: 4037 AN: 362968

Other (OTH) AF: 0.0168 AC: 347 AN: 20658

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0392 AC: 1490 AN: 38018 Hom.: 0 Cov.: 0 AF XY: 0.0344 AC XY: 662 AN XY: 19258

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

African (AFR) AF: 0.0461 AC: 443 AN: 9614

American (AMR) AF: 0.0223 AC: 86 AN: 3848

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 34 AN: 968

East Asian (EAS) AF: 0.00537 AC: 9 AN: 1676

South Asian (SAS) AF: 0.0144 AC: 16 AN: 1110

European-Finnish (FIN) AF: 0.0346 AC: 72 AN: 2078

Middle Eastern (MID) AF: 0.0238 AC: 2 AN: 84

European-Non Finnish (NFE) AF: 0.0449 AC: 805 AN: 17918

Other (OTH) AF: 0.0303 AC: 16 AN: 528

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000554 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.2692+7C>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.2692+7C>G in individuals affected with KCNH2-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 456915). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Likely 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. -

Long QT syndrome Benign:1

Mar 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.7
DANN	Benign	0.91
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.080
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: rs372023163; hg19: chr7-150645525;