Genetic Variant NM_000218.3:c.*264T>C (chr11-2848267-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★). The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.011 ( 15 hom., cov: 33)

Exomes 𝑓: 0.015 ( 86 hom. )

Consequence

KCNQ1
NM_000218.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.33

Publications

3 publications found

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 links:

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 304238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KCNQ1	NM_000218.3	MANE Select	c.*264T>C	3_prime_UTR	Exon 16 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.*264T>C	3_prime_UTR	Exon 15 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.*264T>C	3_prime_UTR	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.*264T>C	3_prime_UTR	Exon 16 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.*264T>C	3_prime_UTR	Exon 16 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.*264T>C	3_prime_UTR	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1751

AN:

152184

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0145

AC:

1499

AN:

103410

AF XY:

0.0145

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 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.:

Cov.:

AF XY:

0.0149

AC XY:

3941

AN XY:

263658

show subpopulations

African (AFR)

AF:

0.00460

AC:

AN:

14136

American (AMR)

AF:

0.0153

AC:

449

AN:

29396

Ashkenazi Jewish (ASJ)

AF:

0.0361

AC:

617

AN:

17088

East Asian (EAS)

AF:

0.0000660

AC:

AN:

30310

South Asian (SAS)

AF:

0.0162

AC:

913

AN:

56436

European-Finnish (FIN)

AF:

0.00357

AC:

108

AN:

30258

Middle Eastern (MID)

AF:

0.0460

AC:

100

AN:

2172

European-Non Finnish (NFE)

AF:

0.0164

AC:

4674

AN:

284412

Other (OTH)

AF:

0.0170

AC:

467

AN:

27512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

399

798

1198

1597

1996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0115

AC:

1747

AN:

152302

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00339

AC:

141

AN:

41574

American (AMR)

AF:

0.0217

AC:

332

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0153

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1009

AN:

67994

Other (OTH)

AF:

0.0189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atrial fibrillation, familial, 3 (1)

Congenital long QT syndrome (1)

Jervell and Lange-Nielsen syndrome 1 (1)

Long QT syndrome 1 (1)

not provided (1)

Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.45

(source)

DANN

Benign

0.40

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over