dbSNP rs45477500: KCNQ1:c.*219G>A (chr11-2848222-G-A) – 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.*219G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 662,384 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 10 hom., cov: 33)

Exomes 𝑓: 0.012 ( 51 hom. )

Consequence

KCNQ1
NM_000218.3 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.216

Publications

2 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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 11-2848222-G-A is Benign according to our data. Variant chr11-2848222-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00973 (1483/152356) while in subpopulation NFE AF = 0.016 (1085/68018). AF 95% confidence interval is 0.0152. There are 10 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 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.*219G>A	3_prime_UTR	Exon 16 of 16	NP_000209.2
KCNQ1	NM_001406836.1		c.*219G>A	3_prime_UTR	Exon 15 of 15	NP_001393765.1
KCNQ1	NM_001406837.1		c.*219G>A	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.*219G>A	3_prime_UTR	Exon 16 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.*219G>A	3_prime_UTR	Exon 16 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.*219G>A	3_prime_UTR	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.00973

AC:

1481

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00318

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.00837

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00496

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00925

AC:

951

AN:

102842

AF XY:

0.00939

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.000765

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00664

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0116

AC:

5918

AN:

510028

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

3112

AN XY:

273608

show subpopulations

African (AFR)

AF:

0.00268

AC:

AN:

14576

American (AMR)

AF:

0.00708

AC:

212

AN:

29930

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

17412

East Asian (EAS)

AF:

0.00

AC:

AN:

31528

South Asian (SAS)

AF:

0.00487

AC:

275

AN:

56426

European-Finnish (FIN)

AF:

0.00524

AC:

166

AN:

31690

Middle Eastern (MID)

AF:

0.00177

AC:

AN:

2258

European-Non Finnish (NFE)

AF:

0.0164

AC:

4887

AN:

297756

Other (OTH)

AF:

0.0111

AC:

315

AN:

28452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

304

608

912

1216

1520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00973

AC:

1483

AN:

152356

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

672

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00317

AC:

132

AN:

41592

American (AMR)

AF:

0.00836

AC:

128

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00538

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0160

AC:

1085

AN:

68018

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

158

237

316

395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0115

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Atrial fibrillation, familial, 3 (1)

Congenital long QT syndrome (1)

Jervell and Lange-Nielsen syndrome 1 (1)

Long QT syndrome 1 (1)

Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.7

(source)

DANN

Benign

0.82

PhyloP100

0.22

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