chr7-150974931-G-T

Variant names:

• chr7-150974931-G-T
• rs199472830
• NM_000238.4:c.87C>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000238.4(KCNH2):​c.87C>A​(p.Phe29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). 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. F29S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.28
• Publications: 23 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: Pathogenic. The variant received 21 ACMG points.

• PS1: Transcript NM_000238.4 (KCNH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 7-150974931-G-T is Pathogenic according to our data. Variant chr7-150974931-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 67538.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.87C>A	p.Phe29Leu	missense	Exon 2 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.87C>A	p.Phe29Leu	missense	Exon 2 of 9	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.-91C>A		5_prime_UTR	Exon 2 of 9	NP_001393684.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.87C>A	p.Phe29Leu	missense	Exon 2 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000713710.1		c.87C>A	p.Phe29Leu	missense	Exon 2 of 15	ENSP00000519013.1	A0AAQ5BGR0
	KCNH2	ENST00000945647.1		c.87C>A	p.Phe29Leu	missense	Exon 2 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452354 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 722062

⚠️ 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: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 85666

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109072

Other (OTH) AF: 0.00 AC: 0 AN: 60066

⚠️ 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.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Long QT syndrome (2)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.027
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.96
MutPred		0.82		Loss of methylation at K28 (P = 0.035)
MVP		1.0
MPC		1.2
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.85
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs199472830; hg19: chr7-150672019;