rs1273257287

Variant names:

• chr11-2445279-C-A
• rs1273257287
• NM_000218.3:c.181C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2445279-C-A
• chr11-2445279-C-G
• chr11-2445279-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000218.3(KCNQ1):​c.181C>A​(p.Pro61Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,303,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P61S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.765
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.181C>A	p.Pro61Thr	missense	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.181C>A	p.Pro61Thr	missense	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.181C>A	p.Pro61Thr	missense	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.181C>A	p.Pro61Thr	missense	Exon 1 of 16	ENSP00000155840.2
	KCNQ1	ENST00000713725.1		c.181C>A	p.Pro61Thr	missense	Exon 1 of 15	ENSP00000519029.1
	KCNQ1	ENST00000646564.2		c.181C>A	p.Pro61Thr	missense	Exon 1 of 11	ENSP00000495806.2

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 4 AN: 149850 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 17 AN: 1153328 Hom.: 0 Cov.: 31 AF XY: 0.0000161 AC XY: 9 AN XY: 559752

African (AFR) AF: 0.00 AC: 0 AN: 23172

American (AMR) AF: 0.0000963 AC: 1 AN: 10382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15052

East Asian (EAS) AF: 0.00 AC: 0 AN: 25846

South Asian (SAS) AF: 0.00 AC: 0 AN: 40414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3224

European-Non Finnish (NFE) AF: 0.0000166 AC: 16 AN: 964554

Other (OTH) AF: 0.00 AC: 0 AN: 46192

GnomAD4 genome AF: 0.0000267 AC: 4 AN: 149850 Hom.: 0 Cov.: 32 AF XY: 0.0000410 AC XY: 3 AN XY: 73116

African (AFR) AF: 0.00 AC: 0 AN: 41042

American (AMR) AF: 0.000266 AC: 4 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67374

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
CardioboostArm	Benign	0.014
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.77
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.33
Sift	Benign	0.088	T
Sift4G	Benign	0.68	T
Polyphen		0.089	B
Vest4		0.15
MutPred		0.25		Gain of phosphorylation at P61 (P = 0.0088)
MVP		0.92
MPC		1.3
ClinPred		0.091	T
GERP RS		1.9
PromoterAI		-0.014	Neutral
Varity_R		0.051
gMVP		0.32
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1273257287; hg19: chr11-2466509;