NM_000238.4:c.2692+7C>G

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.2692+7C>G		splice_region intron	N/A	NP_000229.1
	KCNH2	NM_001406753.1		c.2404+7C>G		splice_region intron	N/A	NP_001393682.1
	KCNH2	NM_172057.3		c.1672+7C>G		splice_region intron	N/A	NP_742054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2692+7C>G		splice_region intron	N/A	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1672+7C>G		splice_region intron	N/A	ENSP00000328531.4
	KCNH2	ENST00000713710.1		c.2626+7C>G		splice_region intron	N/A	ENSP00000519013.1

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;