rs41314366

Variant names:

• chr7-150949990-G-A
• rs41314366
• NM_000238.4:c.2398+178C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-150949990-G-A
• chr7-150949990-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_172056.3(KCNH2):​c.2576C>T​(p.Thr859Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,553,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T859T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KCNH2 NM_172056.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0980
• Publications: 1 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: Benign. The variant received -15 ACMG points.

• PP2: Missense variant in the KCNH2 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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: 3.4405 (above 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=0.005583346).
• BP6: Variant 7-150949990-G-A is Benign according to our data. Variant chr7-150949990-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 124 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172056.3. 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.2398+178C>T		intron	N/A	NP_000229.1
	KCNH2	NM_172056.3		c.2576C>T	p.Thr859Met	missense	Exon 9 of 9	NP_742053.1
	KCNH2	NM_001406755.1		c.2399C>T	p.Thr800Met	missense	Exon 9 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.2398+178C>T		intron	N/A	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.1378+178C>T		intron	N/A	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.1874C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000173 AC: 28 AN: 161984 AF XY: 0.000162

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0000399

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000887

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 142 AN: 1401678 Hom.: 0 Cov.: 31 AF XY: 0.0000997 AC XY: 69 AN XY: 692194

African (AFR) AF: 0.00256 AC: 81 AN: 31648

American (AMR) AF: 0.0000556 AC: 2 AN: 35986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35674

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49436

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5694

European-Non Finnish (NFE) AF: 0.0000444 AC: 48 AN: 1080580

Other (OTH) AF: 0.0000517 AC: 3 AN: 58080

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152258 Hom.: 1 Cov.: 31 AF XY: 0.000819 AC XY: 61 AN XY: 74446

African (AFR) AF: 0.00274 AC: 114 AN: 41542

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00130 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000714 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiac arrhythmia (1)
-	-	1	KCNH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	0.25	D
PhyloP100		-0.098
REVEL	Benign	0.26
Sift4G	Benign	0.24	T
Vest4		0.15
MVP		0.082
ClinPred		0.016	T
GERP RS		-5.1
Mutation Taster		=99/1	polymorphism

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: rs41314366; hg19: chr7-150647078; COSMIC: COSV100060755;