7-150948446-T-G

Variant names:

• chr7-150948446-T-G
• rs1805123
• NM_000238.4:c.2690A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000238.4(KCNH2):​c.2690A>C​(p.Lys897Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,097,454 control chromosomes in the GnomAD database, including 40,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K897R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (2640 hom., cov: 27)
  • Exomes 𝑓: 0.32 (37449 hom.)
• Consequence: KCNH2 NM_000238.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001136
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 2.77
• Publications: 207 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 -19 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=0.0014851391).
• BP6: Variant 7-150948446-T-G is Benign according to our data. Variant chr7-150948446-T-G is described in ClinVar as Benign. ClinVar VariationId is 67427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

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.2690A>C	p.Lys897Thr	missense splice_region	Exon 11 of 15	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.2402A>C	p.Lys801Thr	missense splice_region	Exon 9 of 13	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.1670A>C	p.Lys557Thr	missense splice_region	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.2690A>C	p.Lys897Thr	missense splice_region	Exon 11 of 15	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1670A>C	p.Lys557Thr	missense splice_region	Exon 7 of 11	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.2624A>C	p.Lys875Thr	missense splice_region	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.210 AC: 24594 AN: 116886 Hom.: 2636 Cov.: 27

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0729

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.181 AC: 43182 AN: 238268 AF XY: 0.191

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0477

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.325 AC: 318343 AN: 980560 Hom.: 37449 Cov.: 28 AF XY: 0.320 AC XY: 159155 AN XY: 497778

African (AFR) AF: 0.0631 AC: 1144 AN: 18118

American (AMR) AF: 0.139 AC: 5295 AN: 37986

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 5310 AN: 17970

East Asian (EAS) AF: 0.109 AC: 1786 AN: 16328

South Asian (SAS) AF: 0.233 AC: 17350 AN: 74426

European-Finnish (FIN) AF: 0.252 AC: 7641 AN: 30272

Middle Eastern (MID) AF: 0.283 AC: 1227 AN: 4332

European-Non Finnish (NFE) AF: 0.359 AC: 266219 AN: 742380

Other (OTH) AF: 0.319 AC: 12371 AN: 38748

GnomAD4 genome AF: 0.210 AC: 24588 AN: 116894 Hom.: 2640 Cov.: 27 AF XY: 0.208 AC XY: 11756 AN XY: 56486

African (AFR) AF: 0.0586 AC: 1698 AN: 28986

American (AMR) AF: 0.211 AC: 2441 AN: 11596

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 677 AN: 2948

East Asian (EAS) AF: 0.0727 AC: 245 AN: 3368

South Asian (SAS) AF: 0.266 AC: 973 AN: 3664

European-Finnish (FIN) AF: 0.256 AC: 1646 AN: 6432

Middle Eastern (MID) AF: 0.274 AC: 63 AN: 230

European-Non Finnish (NFE) AF: 0.283 AC: 16237 AN: 57310

Other (OTH) AF: 0.229 AC: 377 AN: 1644

Alfa AF: 0.210 Hom.: 11563

Bravo AF: 0.155

TwinsUK AF: 0.247 AC: 917

ALSPAC AF: 0.242 AC: 933

ESP6500AA AF: 0.0452 AC: 199

ESP6500EA AF: 0.233 AC: 2000

ExAC AF: 0.180 AC: 21831

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (5)
-	-	2	Long QT syndrome (2)
-	-	2	Long QT syndrome 2 (2)
-	-	1	Atrial fibrillation (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.46
Sift	Benign	0.23	T
Sift4G	Benign	0.22	T
Polyphen		0.25	B
Vest4		0.53
MPC		0.20
ClinPred		0.013	T
GERP RS		-0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.084
gMVP		0.79
Mutation Taster		=45/55	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.024
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: rs1805123; hg19: chr7-150645534; COSMIC: COSV51125898; COSMIC: COSV51125898;