rs199472826

Variant names:

• chr7-150977849-A-C
• rs199472826
• NM_000238.4:c.65T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-150977849-A-C
• chr7-150977849-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_000238.4(KCNH2):​c.65T>G​(p.Phe22Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F22S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.06
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_000238.4
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: 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.65T>G	p.Phe22Cys	missense	Exon 1 of 15	NP_000229.1
	KCNH2	NM_172056.3		c.65T>G	p.Phe22Cys	missense	Exon 1 of 9	NP_742053.1
	KCNH2	NR_176254.1		n.473T>G		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.65T>G	p.Phe22Cys	missense	Exon 1 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.65T>G	p.Phe22Cys	missense	Exon 1 of 15	ENSP00000519013.1
	KCNH2	ENST00000945647.1		c.65T>G	p.Phe22Cys	missense	Exon 1 of 14	ENSP00000615706.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 135928 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000651 AC: 9 AN: 1382130 Hom.: 0 Cov.: 33 AF XY: 0.00000873 AC XY: 6 AN XY: 686918

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

African (AFR) AF: 0.0000321 AC: 1 AN: 31188

American (AMR) AF: 0.0000472 AC: 2 AN: 42378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23434

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32754

South Asian (SAS) AF: 0.00 AC: 0 AN: 84694

European-Finnish (FIN) AF: 0.0000453 AC: 2 AN: 44154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4362

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1063964

Other (OTH) AF: 0.00 AC: 0 AN: 55202

⚠️ 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: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 136024 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 65744

African (AFR) AF: 0.00 AC: 0 AN: 36254

American (AMR) AF: 0.00 AC: 0 AN: 13488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3298

East Asian (EAS) AF: 0.00 AC: 0 AN: 4244

South Asian (SAS) AF: 0.00 AC: 0 AN: 3958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63408

Other (OTH) AF: 0.00 AC: 0 AN: 1858

ClinVar

ClinVar submissions as Germline

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	1.0
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.58		Gain of methylation at K21 (P = 0.0385)
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		2.3
PromoterAI		-0.026	Neutral
Varity_R		0.85
gMVP		0.99
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: 1

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

Other links and lift over

dbSNP: rs199472826; hg19: chr7-150674937;