11-2444714-C-G

Position:

• chr11-2444714-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000496887.7(KCNQ1):​c.23+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (11 hom., cov: 12)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 ENST00000496887.7 splice_region, intron
• Scores: Splicing: ADA: 0.00004150
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-2444714-C-G is Benign according to our data. Variant chr11-2444714-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1201132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (1346/66666) while in subpopulation NFE AF= 0.0286 (1004/35082). AF 95% confidence interval is 0.0271. There are 11 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 12. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.2444714C>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000496887.7	c.23+6C>G		splice_region_variant, intron_variant		5		ENSP00000434560.2

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 1346 AN: 66640 Hom.: 11 Cov.: 12

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.0752

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.000534

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000568

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0128

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0202 AC: 1346 AN: 66666 Hom.: 11 Cov.: 12 AF XY: 0.0199 AC XY: 610 AN XY: 30676

Gnomad4 AFR AF: 0.00546

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.000534

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000567

Gnomad4 FIN AF: 0.0538

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0127

Alfa AF: 0.0134 Hom.: 3

Bravo AF: 0.0114

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.9
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0080

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45478095; hg19: chr11-2465944;