rs199473441

Variant names:

• chr11-2445099-A-G
• rs199473441
• NM_000218.3:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-2445099-A-G
• chr11-2445099-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001406837.1(KCNQ1):​c.-362A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_001406837.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.187
• Publications: 7 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

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.1A>G	p.Met1?	start_lost	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406837.1		c.-362A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001393766.1
	KCNQ1	NM_001406836.1		c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000155840.2
	KCNQ1	ENST00000910997.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 932718 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 438852

African (AFR) AF: 0.00 AC: 0 AN: 17754

American (AMR) AF: 0.00 AC: 0 AN: 3934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8120

East Asian (EAS) AF: 0.00 AC: 0 AN: 12508

South Asian (SAS) AF: 0.00 AC: 0 AN: 19850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2076

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 824644

Other (OTH) AF: 0.00 AC: 0 AN: 32890

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.017	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.84	D
PhyloP100		-0.19
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.24
MutPred		0.96		Gain of MoRF binding (P = 0.1682)
MVP		0.90
ClinPred		0.50	T
GERP RS		2.1
PromoterAI		-0.12	Neutral
Varity_R		0.92
gMVP		0.52
Mutation Taster		=4/196	disease causing

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: rs199473441; hg19: chr11-2466329;