7-150958059-C-T

Variant names:

• chr7-150958059-C-T
• rs199472884
• NM_000238.4:c.916G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_000238.4(KCNH2):​c.916G>A​(p.Gly306Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000902 in 1,108,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G306W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.251
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150958059-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 67544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.916G>A	p.Gly306Arg	missense splice_region	Exon 4 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.628G>A	p.Gly210Arg	missense splice_region	Exon 2 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172056.3		c.916G>A	p.Gly306Arg	missense splice_region	Exon 4 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.916G>A	p.Gly306Arg	missense splice_region	Exon 4 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.916G>A	p.Gly306Arg	missense splice_region	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000713701.1		c.616G>A	p.Gly206Arg	missense splice_region	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.02e-7 AC: 1 AN: 1108190 Hom.: 0 Cov.: 31 AF XY: 0.00000190 AC XY: 1 AN XY: 525060

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

African (AFR) AF: 0.00 AC: 0 AN: 22816

American (AMR) AF: 0.00 AC: 0 AN: 10038

Ashkenazi Jewish (ASJ) AF: 0.0000683 AC: 1 AN: 14636

East Asian (EAS) AF: 0.00 AC: 0 AN: 26604

South Asian (SAS) AF: 0.00 AC: 0 AN: 24698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 938616

Other (OTH) AF: 0.00 AC: 0 AN: 45110

⚠️ 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 Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.25
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.038	D
Polyphen		0.89	P
Vest4		0.48
MutPred		0.75		Gain of solvent accessibility (P = 0.019)
MVP		1.0
MPC		1.7
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.68
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199472884; hg19: chr7-150655147;