7-150945521-TAC-T

Variant names:

• chr7-150945521-TAC-T
• rs41313749
• NM_000238.4:c.3331-9_3331-8delGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000238.4(KCNH2):​c.3331-9_3331-8delGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,557,036 control chromosomes in the GnomAD database, including 125 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: KCNH2 NM_000238.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.08
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 7-150945521-TAC-T is Benign according to our data. Variant chr7-150945521-TAC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 200266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 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.3331-9_3331-8delGT		splice_region intron	N/A	NP_000229.1	A0A090N8Q0
	KCNH2	NM_001406753.1		c.3043-9_3043-8delGT		splice_region intron	N/A	NP_001393682.1	Q12809-7
	KCNH2	NM_172057.3		c.2311-9_2311-8delGT		splice_region intron	N/A	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.3331-9_3331-8delGT		splice_region intron	N/A	ENSP00000262186.5	Q12809-1
	KCNH2	ENST00000330883.9	TSL:1	c.2311-9_2311-8delGT		splice_region intron	N/A	ENSP00000328531.4	Q12809-2
	KCNH2	ENST00000713710.1		c.3265-9_3265-8delGT		splice_region intron	N/A	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2336 AN: 151260 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00367 AC: 593 AN: 161778 AF XY: 0.00260

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00152 AC: 2139 AN: 1405658 Hom.: 51 AF XY: 0.00131 AC XY: 912 AN XY: 693924

African (AFR) AF: 0.0552 AC: 1762 AN: 31898

American (AMR) AF: 0.00294 AC: 107 AN: 36382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 36318

South Asian (SAS) AF: 0.000113 AC: 9 AN: 79632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49266

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5700

European-Non Finnish (NFE) AF: 0.0000563 AC: 61 AN: 1082870

Other (OTH) AF: 0.00326 AC: 190 AN: 58364

GnomAD4 genome AF: 0.0154 AC: 2334 AN: 151378 Hom.: 74 Cov.: 32 AF XY: 0.0150 AC XY: 1110 AN XY: 73908

African (AFR) AF: 0.0536 AC: 2205 AN: 41172

American (AMR) AF: 0.00591 AC: 90 AN: 15240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67888

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00764 Hom.: 2

Bravo AF: 0.0174

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Long QT syndrome (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	not provided (1)
-	-	1	Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41313749; hg19: chr7-150642609;