7-150974946-G-C

Variant names:

• chr7-150974946-G-C
• rs72549419
• NM_000238.4:c.77-5C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000238.4(KCNH2):​c.77-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,589,412 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Scores: Splicing: ADA: 0.0007058
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.934
• Publications: 0 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), G2P, Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-150974946-G-C is Benign according to our data. Variant chr7-150974946-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359317.
• BS2: High AC in GnomAd4 at 38 AD gene.

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.77-5C>G		splice_region intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.77-5C>G		splice_region intron	N/A	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.-101-5C>G		splice_region intron	N/A	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.77-5C>G		splice_region intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.77-5C>G		splice_region intron	N/A	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.77-5C>G		splice_region intron	N/A	ENSP00000615706.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152196 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000427 AC: 92 AN: 215648 AF XY: 0.000558

Gnomad AFR exome AF: 0.0000767

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.0000702

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000903

GnomAD4 exome AF: 0.000370 AC: 532 AN: 1437100 Hom.: 5 Cov.: 33 AF XY: 0.000438 AC XY: 312 AN XY: 712888

African (AFR) AF: 0.0000910 AC: 3 AN: 32956

American (AMR) AF: 0.000555 AC: 24 AN: 43276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.0000773 AC: 3 AN: 38806

South Asian (SAS) AF: 0.00143 AC: 121 AN: 84728

European-Finnish (FIN) AF: 0.000178 AC: 8 AN: 45060

Middle Eastern (MID) AF: 0.00299 AC: 17 AN: 5682

European-Non Finnish (NFE) AF: 0.000300 AC: 330 AN: 1101308

Other (OTH) AF: 0.000437 AC: 26 AN: 59452

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152312 Hom.: 3 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74480

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000294 Hom.: 0

Bravo AF: 0.000208

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	KCNH2-related disorder (1)
-	-	1	Long QT syndrome (1)
-	1	-	Long QT syndrome 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.1
DANN	Benign	0.79
PhyloP100		-0.93
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00071
dbscSNV1_RF	Benign	0.13
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: rs72549419; hg19: chr7-150672034;