7-150948519-C-T

Variant names:

• chr7-150948519-C-T
• rs41314354
• NM_000238.4:c.2617G>A

Variant summary

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

The NM_000238.4(KCNH2):​c.2617G>A​(p.Gly873Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G873R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.67
• Publications: 10 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: Benign. The variant received -15 ACMG points.

• 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=0.035688758).
• BP6: Variant 7-150948519-C-T is Benign according to our data. Variant chr7-150948519-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 67419.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_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.2617G>A	p.Gly873Ser	missense	Exon 11 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2329G>A	p.Gly777Ser	missense	Exon 9 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1597G>A	p.Gly533Ser	missense	Exon 7 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2617G>A	p.Gly873Ser	missense	Exon 11 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1597G>A	p.Gly533Ser	missense	Exon 7 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2551G>A	p.Gly851Ser	missense	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

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

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000188 AC: 47 AN: 250272 AF XY: 0.000155

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1461448 Hom.: 0 Cov.: 37 AF XY: 0.000100 AC XY: 73 AN XY: 727074

African (AFR) AF: 0.00239 AC: 80 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111992

Other (OTH) AF: 0.0000497 AC: 3 AN: 60390

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152258 Hom.: 1 Cov.: 31 AF XY: 0.000833 AC XY: 62 AN XY: 74460

African (AFR) AF: 0.00270 AC: 112 AN: 41546

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000914

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	KCNH2-related disorder (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)
-	-	1	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
CardioboostArm	Benign	0.0000021
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	-0.14	N
PhyloP100		1.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.48
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Polyphen		0.26	B
Vest4		0.21
MVP		0.89
MPC		0.17
ClinPred		0.026	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.041
gMVP		0.63
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41314354; hg19: chr7-150645607;