NM_000218.3:c.1800G>A

Variant names:

• chr11-2847772-G-A
• rs147091980
• NM_000218.3:c.1800G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000218.3(KCNQ1):​c.1800G>A​(p.Thr600Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,573,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: -3.42
• Publications: 1 publications found

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-2847772-G-A is Benign according to our data. Variant chr11-2847772-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163744.
• BP7: Synonymous conserved (PhyloP=-3.42 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. 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
	KCNQ1	NM_000218.3	MANE Select	c.1800G>A	p.Thr600Thr	synonymous	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1704G>A	p.Thr568Thr	synonymous	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1530G>A	p.Thr510Thr	synonymous	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1800G>A	p.Thr600Thr	synonymous	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1419G>A	p.Thr473Thr	synonymous	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1797G>A	p.Thr599Thr	synonymous	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000275 AC: 51 AN: 185222 AF XY: 0.000231

Gnomad AFR exome AF: 0.0000897

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.000701 AC: 997 AN: 1421300 Hom.: 1 Cov.: 31 AF XY: 0.000694 AC XY: 488 AN XY: 703312

African (AFR) AF: 0.0000917 AC: 3 AN: 32702

American (AMR) AF: 0.000280 AC: 11 AN: 39284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25434

East Asian (EAS) AF: 0.000851 AC: 32 AN: 37624

South Asian (SAS) AF: 0.00 AC: 0 AN: 81046

European-Finnish (FIN) AF: 0.0000404 AC: 2 AN: 49548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.000830 AC: 906 AN: 1091046

Other (OTH) AF: 0.000730 AC: 43 AN: 58900

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74462

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.000327 AC: 5 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000412

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Long QT syndrome (2)
-	1	-	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Jervell and Lange-Nielsen syndrome 1 (1)
-	1	-	Long QT syndrome 1 (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.89
PhyloP100		-3.4
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: rs147091980; hg19: chr11-2869002;