7-150949840-G-A

Variant names:

• chr7-150949840-G-A
• rs41307289
• NM_000238.4:c.2398+328C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172056.3(KCNH2):​c.*59C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,271,754 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (154 hom.)
• Consequence: KCNH2 NM_172056.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.79
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-150949840-G-A is Benign according to our data. Variant chr7-150949840-G-A is described in ClinVar as Benign. ClinVar VariationId is 1290932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0746 is higher than 0.05.

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+328C>T		intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_172056.3		c.*59C>T		3_prime_UTR	Exon 9 of 9	NP_742053.1	Q12809-5
	KCNH2	NM_001406755.1		c.*59C>T		3_prime_UTR	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+328C>T		intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.1378+328C>T		intron	N/A	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000461280.2	TSL:1	n.2024C>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152166 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0810

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00461 AC: 5156 AN: 1119470 Hom.: 154 Cov.: 30 AF XY: 0.00590 AC XY: 3180 AN XY: 539036

African (AFR) AF: 0.000508 AC: 12 AN: 23610

American (AMR) AF: 0.0150 AC: 258 AN: 17186

Ashkenazi Jewish (ASJ) AF: 0.000315 AC: 4 AN: 12704

East Asian (EAS) AF: 0.0863 AC: 1439 AN: 16670

South Asian (SAS) AF: 0.0458 AC: 2820 AN: 61580

European-Finnish (FIN) AF: 0.00312 AC: 86 AN: 27570

Middle Eastern (MID) AF: 0.00353 AC: 15 AN: 4244

European-Non Finnish (NFE) AF: 0.000273 AC: 250 AN: 914294

Other (OTH) AF: 0.00654 AC: 272 AN: 41612

GnomAD4 genome AF: 0.00547 AC: 833 AN: 152284 Hom.: 18 Cov.: 31 AF XY: 0.00673 AC XY: 501 AN XY: 74470

African (AFR) AF: 0.000313 AC: 13 AN: 41562

American (AMR) AF: 0.00699 AC: 107 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0810 AC: 419 AN: 5176

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00523

Asia WGS AF: 0.0430 AC: 148 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.23
DANN	Benign	0.41
PhyloP100		-2.8
Mutation Taster		=100/0	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: rs41307289; hg19: chr7-150646928;