rs138776684

Variant names:

• chr7-150957380-G-A
• rs138776684
• NM_000238.4:c.1039C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_000238.4(KCNH2):​c.1039C>T​(p.Pro347Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,000 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P347L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:14 O:1
• Conservation: PhyloP100: 0.436
• Publications: 24 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_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010891318).
• BP6: Variant 7-150957380-G-A is Benign according to our data. Variant chr7-150957380-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67163.
• BS2: High AC in GnomAd4 at 97 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1039C>T	p.Pro347Ser	missense	Exon 5 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.751C>T	p.Pro251Ser	missense	Exon 3 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.1039C>T	p.Pro347Ser	missense	Exon 5 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1039C>T	p.Pro347Ser	missense	Exon 5 of 15	ENSP00000262186.5
	KCNH2	ENST00000713710.1		c.1039C>T	p.Pro347Ser	missense	Exon 5 of 15	ENSP00000519013.1
	KCNH2	ENST00000713701.1		c.739C>T	p.Pro247Ser	missense	Exon 4 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152268 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00106 AC: 265 AN: 250142 AF XY: 0.00120

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.00114 AC: 1659 AN: 1461614 Hom.: 8 Cov.: 32 AF XY: 0.00120 AC XY: 872 AN XY: 727102

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00282 AC: 243 AN: 86218

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53410

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00115 AC: 1275 AN: 1111846

Other (OTH) AF: 0.00111 AC: 67 AN: 60380

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152386 Hom.: 0 Cov.: 33 AF XY: 0.000751 AC XY: 56 AN XY: 74526

African (AFR) AF: 0.000264 AC: 11 AN: 41590

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68044

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000567

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	3	1	Long QT syndrome 2 (4)
-	1	2	Long QT syndrome (3)
-	-	3	not specified (3)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	KCNH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.44
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.55
Sift	Benign	0.46	T
Sift4G	Benign	0.71	T
Polyphen		0.76	P
Vest4		0.22
MVP		0.98
MPC		1.3
ClinPred		0.025	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.75
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138776684; hg19: chr7-150654468; COSMIC: COSV106087201; COSMIC: COSV106087201;