rs532941548

Variant names:

• chr11-2445094-T-C
• rs532941548
• NM_000218.3:c.-5T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000218.3(KCNQ1):​c.-5T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,077,632 control chromosomes in the GnomAD database, including 13 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 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (12 hom.)
• Consequence: KCNQ1 NM_000218.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:11
• Conservation: PhyloP100: -1.90
• Publications: 0 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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-2445094-T-C is Benign according to our data. Variant chr11-2445094-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138009.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.-5T>C		5_prime_UTR	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.-5T>C		5_prime_UTR	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.-367T>C		5_prime_UTR	Exon 1 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.-5T>C		5_prime_UTR	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.-5T>C		5_prime_UTR	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.-5T>C		5_prime_UTR	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 395 AN: 147596 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000806

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00588

GnomAD2 exomes AF: 0.00161 AC: 4 AN: 2492 AF XY: 0.00176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00452 AC: 4207 AN: 929928 Hom.: 12 Cov.: 30 AF XY: 0.00454 AC XY: 1985 AN XY: 437024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000621 AC: 11 AN: 17702

American (AMR) AF: 0.00158 AC: 6 AN: 3806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8024

East Asian (EAS) AF: 0.00 AC: 0 AN: 12392

South Asian (SAS) AF: 0.00328 AC: 64 AN: 19516

European-Finnish (FIN) AF: 0.00110 AC: 12 AN: 10936

Middle Eastern (MID) AF: 0.00146 AC: 3 AN: 2056

European-Non Finnish (NFE) AF: 0.00486 AC: 4001 AN: 822766

Other (OTH) AF: 0.00336 AC: 110 AN: 32730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00267 AC: 395 AN: 147704 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 172 AN XY: 71994

African (AFR) AF: 0.000803 AC: 33 AN: 41080

American (AMR) AF: 0.00148 AC: 22 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00144 AC: 13 AN: 9048

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

European-Non Finnish (NFE) AF: 0.00454 AC: 300 AN: 66146

Other (OTH) AF: 0.00582 AC: 12 AN: 2062

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00255

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	5	not specified (5)
-	1	-	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (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	-0.78
CADD	Benign	9.5
DANN	Benign	0.72
PhyloP100		-1.9
PromoterAI		0.13	Neutral
Mutation Taster		=299/1	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: rs532941548; hg19: chr11-2466324;