GeneBe

rs45579540

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000218.3(KCNQ1):​c.*264T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 644,022 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.011 ( 15 hom., cov: 33)
Exomes 𝑓: 0.015 ( 86 hom. )

Consequence

KCNQ1
NM_000218.3 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, single submitter B:5

Conservation

PhyloP100: -1.33
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]
KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.95).
BP6
Variant 11-2848267-T-C is Benign according to our data. Variant chr11-2848267-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 304238.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0115 (1747/152302) while in subpopulation AMR AF= 0.0217 (332/15310). AF 95% confidence interval is 0.0198. There are 15 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 15 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.*264T>C 3_prime_UTR_variant 16/16 ENST00000155840.12
KCNQ1-AS1NR_130721.1 linkuse as main transcriptn.778-7825A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.*264T>C 3_prime_UTR_variant 16/161 NM_000218.3 P1P51787-1
KCNQ1-AS1ENST00000440887.2 linkuse as main transcriptn.777-7825A>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0115
AC:
1751
AN:
152184
Hom.:
15
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00343
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0218
Gnomad ASJ
AF:
0.0337
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0155
Gnomad FIN
AF:
0.00141
Gnomad MID
AF:
0.0570
Gnomad NFE
AF:
0.0148
Gnomad OTH
AF:
0.0191
GnomAD3 exomes
AF:
0.0145
AC:
1499
AN:
103410
Hom.:
21
AF XY:
0.0145
AC XY:
813
AN XY:
56092
show subpopulations
Gnomad AFR exome
AF:
0.00173
Gnomad AMR exome
AF:
0.0145
Gnomad ASJ exome
AF:
0.0366
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0165
Gnomad FIN exome
AF:
0.00402
Gnomad NFE exome
AF:
0.0164
Gnomad OTH exome
AF:
0.0239
GnomAD4 exome
AF:
0.0150
AC:
7395
AN:
491720
Hom.:
86
Cov.:
0
AF XY:
0.0149
AC XY:
3941
AN XY:
263658
show subpopulations
Gnomad4 AFR exome
AF:
0.00460
Gnomad4 AMR exome
AF:
0.0153
Gnomad4 ASJ exome
AF:
0.0361
Gnomad4 EAS exome
AF:
0.0000660
Gnomad4 SAS exome
AF:
0.0162
Gnomad4 FIN exome
AF:
0.00357
Gnomad4 NFE exome
AF:
0.0164
Gnomad4 OTH exome
AF:
0.0170
GnomAD4 genome
AF:
0.0115
AC:
1747
AN:
152302
Hom.:
15
Cov.:
33
AF XY:
0.0110
AC XY:
820
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00339
Gnomad4 AMR
AF:
0.0217
Gnomad4 ASJ
AF:
0.0337
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0153
Gnomad4 FIN
AF:
0.00141
Gnomad4 NFE
AF:
0.0148
Gnomad4 OTH
AF:
0.0189
Alfa
AF:
0.0161
Hom.:
4
Bravo
AF:
0.0126
Asia WGS
AF:
0.00866
AC:
30
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Atrial fibrillation, familial, 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Jervell and Lange-Nielsen syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Short QT syndrome type 2 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Congenital long QT syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.95
CADD
Benign
0.45
DANN
Benign
0.40

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: rs45579540; hg19: chr11-2869497; API