chr7-150948437-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -0.817

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 456915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948437-G-C is described in Lovd as [Benign].

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
KCNH2	ENST00000330883.9	c.1672+7C>G		splice_region_variant, intron_variant	Intron 7 of 10	1		ENSP00000328531.4
KCNH2	ENST00000684241.1	n.3525+7C>G		splice_region_variant, intron_variant	Intron 9 of 12

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1490 AN: 37994 Hom.: 0 Cov.: 0 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.0333

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.0392

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.0167

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.0168

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

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.00537

Gnomad4 SAS AF: 0.0144

Gnomad4 FIN AF: 0.0346

Gnomad4 NFE AF: 0.0449

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.000554 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs372023163; hg19: chr7-150645525;