rs371488379

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000218.3(KCNQ1):​c.1394-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 splice_region, splice_polypyrimidine_tract, intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.605
Variant links:
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]
KCNQ1OT1 (HGNC:6295): (KCNQ1 opposite strand/antisense transcript 1) Human chromosomal region 11p15.5 contains two clusters of epigenetically-regulated genes that are expressed from only one chromosome in a parent-of-origin manner. Each cluster, or imprinted domain, is regulated by a functionally independent imprinting control region (ICR). The human CDKN1C/KCNQ1OT1 domain is regulated by an ICR located in an intron of KCNQ1, and contains at least eight genes that are expressed exclusively or preferentially from the maternally-inherited allele. The DNA of the ICR is specifically methylated on the maternally-inherited chromosome, and unmethylated on the paternally-inherited chromosome. The ICR contains the promoter of the KCNQ1OT1 gene that is exclusively expressed from the paternal allele. The KCNQ1OT1 transcript is the antisense to the KCNQ1 gene and is a unspliced long non-coding RNA. It interacts with chromatin and regulates transcription of multiple target genes through epigenetic modifications. The transcript is abnormally expressed from both chromosomes in most patients with Beckwith-Wiedemann syndrome, and the transcript also plays an important role in colorectal carcinogenesis. [provided by RefSeq, Apr 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.69).
BP6
Variant 11-2661953-C-A is Benign according to our data. Variant chr11-2661953-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.1394-8C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000155840.12 NP_000209.2
KCNQ1OT1NR_002728.3 linkuse as main transcriptn.38046G>T non_coding_transcript_exon_variant 1/1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.1394-8C>A splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_000218.3 ENSP00000155840 P1P51787-1
KCNQ1OT1ENST00000710656.1 linkuse as main transcriptn.376-20838G>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251354
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000835
AC:
122
AN:
1461854
Hom.:
0
Cov.:
34
AF XY:
0.0000784
AC XY:
57
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 05, 2013Variant classified as Uncertain Significance - Favor Benign. The c.1394-8C>A var iant in KCNQ1 has not been reported in individuals with hearing loss or in large population studies. This variant is located in the 3' splice region but not in the invariant ?1/-2 positions. Computational tools do not suggest an impact to s plicing; however, this information is not predictive enough to rule out pathogen icity. In summary, the clinical significance of this variant cannot be determine d with certainty; however, we would lean towards a more likely benign role based on a lack of splicing impact predicted by computational tools. -
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.37
DANN
Benign
0.59

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371488379; hg19: chr11-2683183; API