chr7-150974810-G-A

Variant names:

• chr7-150974810-G-A
• rs199473418
• NM_000238.4:c.208C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000238.4(KCNH2):​c.208C>T​(p.His70Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,084 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H70N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• 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), 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150974809-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67363.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, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.208C>T	p.His70Tyr	missense_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.208C>T	p.His70Tyr	missense_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000713710.1	c.208C>T	p.His70Tyr	missense_variant	Exon 2 of 15			ENSP00000519013.1
KCNH2	ENST00000532957.5	n.431C>T		non_coding_transcript_exon_variant	Exon 2 of 9	2
KCNH2	ENST00000713700.1	n.166C>T		non_coding_transcript_exon_variant	Exon 2 of 9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453084 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 722392

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108298

Other (OTH) AF: 0.0000167 AC: 1 AN: 59882

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
CardioboostArm	Benign	0.00083
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.59	D;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	-0.045	N;.
PhyloP100		1.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.80	N;.
REVEL	Uncertain	0.56
Sift	Benign	0.73	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.032	B;.
Vest4		0.43
MutPred		0.58		Gain of phosphorylation at H70 (P = 0.0695);.;
MVP		0.85
MPC		1.2
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.34
gMVP		0.94
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs199473418; hg19: chr7-150671898;