11-2847847-C-T

Variant names:

• chr11-2847847-C-T
• rs112113213
• NM_000218.3:c.1875C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000218.3(KCNQ1):​c.1875C>T​(p.Pro625Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,570,382 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P625P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KCNQ1 NM_000218.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -2.27
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-2847847-C-T is Benign according to our data. Variant chr11-2847847-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237226.
• BP7: Synonymous conserved (PhyloP=-2.27 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.1875C>T	p.Pro625Pro	synonymous	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1779C>T	p.Pro593Pro	synonymous	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1605C>T	p.Pro535Pro	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.1875C>T	p.Pro625Pro	synonymous	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1494C>T	p.Pro498Pro	synonymous	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1872C>T	p.Pro624Pro	synonymous	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000201 AC: 36 AN: 178682 AF XY: 0.000135

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.000214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000293

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000688

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 171 AN: 1418058 Hom.: 1 Cov.: 31 AF XY: 0.000113 AC XY: 79 AN XY: 701296

African (AFR) AF: 0.00209 AC: 68 AN: 32556

American (AMR) AF: 0.000153 AC: 6 AN: 39094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.000564 AC: 21 AN: 37254

South Asian (SAS) AF: 0.000136 AC: 11 AN: 80800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49200

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5716

European-Non Finnish (NFE) AF: 0.0000184 AC: 20 AN: 1089460

Other (OTH) AF: 0.000716 AC: 42 AN: 58622

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152324 Hom.: 2 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74490

African (AFR) AF: 0.00147 AC: 61 AN: 41572

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

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

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Long QT syndrome (2)
-	1	1	not provided (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	KCNQ1-related disorder (1)
-	-	1	Long QT syndrome 1 (1)
-	-	1	not specified (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.19
DANN	Benign	0.69
PhyloP100		-2.3
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: rs112113213; hg19: chr11-2869077;