11-2445289-C-T

Variant names:

• chr11-2445289-C-T
• rs2522018
• NM_000218.3:c.191C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001406837.1(KCNQ1):​c.-172C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000829 in 1,206,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: KCNQ1 NM_001406837.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.401
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25351667).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406837.1. 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.191C>T	p.Pro64Leu	missense	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406837.1		c.-172C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001393766.1
	KCNQ1	NM_001406836.1		c.191C>T	p.Pro64Leu	missense	Exon 1 of 15	NP_001393765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.191C>T	p.Pro64Leu	missense	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.191C>T	p.Pro64Leu	missense	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.191C>T	p.Pro64Leu	missense	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.29e-7 AC: 1 AN: 1206588 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 589500

African (AFR) AF: 0.00 AC: 0 AN: 24592

American (AMR) AF: 0.00 AC: 0 AN: 15736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17556

East Asian (EAS) AF: 0.00 AC: 0 AN: 27366

South Asian (SAS) AF: 0.00 AC: 0 AN: 50048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3646

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 991878

Other (OTH) AF: 0.00 AC: 0 AN: 48850

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostArm	Benign	0.0052
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.40
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.35
Sift	Benign	0.066	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.27		Loss of glycosylation at P64 (P = 0.0047)
MVP		0.91
MPC		1.2
ClinPred		0.079	T
GERP RS		1.4
PromoterAI		-0.0038	Neutral
Varity_R		0.034
gMVP		0.30
Mutation Taster		=82/18	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: rs2522018; hg19: chr11-2466519;