chr11-2848878-A-G

Variant names:

• chr11-2848878-A-G
• rs8234
• NM_000218.3:c.*875A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000218.3(KCNQ1):​c.*875A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 453,932 control chromosomes in the GnomAD database, including 38,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12571 hom., cov: 34)
  • Exomes 𝑓: 0.39 (26039 hom.)
• Consequence: KCNQ1 NM_000218.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.637
• Publications: 31 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 11-2848878-A-G is Benign according to our data. Variant chr11-2848878-A-G is described in ClinVar as Benign. ClinVar VariationId is 304262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.*875A>G		3_prime_UTR	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.*875A>G		3_prime_UTR	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.*875A>G		3_prime_UTR	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.*875A>G		3_prime_UTR	Exon 16 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.*875A>G		3_prime_UTR	Exon 16 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713724.1		n.*2872A>G		non_coding_transcript_exon	Exon 16 of 16	ENSP00000519028.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59445 AN: 152012 Hom.: 12562 Cov.: 34

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.446 AC: 58181 AN: 130514 AF XY: 0.441

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.872

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.395 AC: 119100 AN: 301802 Hom.: 26039 Cov.: 0 AF XY: 0.400 AC XY: 68770 AN XY: 171994

African (AFR) AF: 0.425 AC: 3639 AN: 8554

American (AMR) AF: 0.552 AC: 15059 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 4108 AN: 10786

East Asian (EAS) AF: 0.870 AC: 8009 AN: 9210

South Asian (SAS) AF: 0.478 AC: 28525 AN: 59650

European-Finnish (FIN) AF: 0.367 AC: 4544 AN: 12374

Middle Eastern (MID) AF: 0.390 AC: 449 AN: 1150

European-Non Finnish (NFE) AF: 0.311 AC: 49382 AN: 158762

Other (OTH) AF: 0.383 AC: 5385 AN: 14042

GnomAD4 genome AF: 0.391 AC: 59495 AN: 152130 Hom.: 12571 Cov.: 34 AF XY: 0.399 AC XY: 29669 AN XY: 74360

African (AFR) AF: 0.424 AC: 17598 AN: 41482

American (AMR) AF: 0.475 AC: 7264 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1335 AN: 3472

East Asian (EAS) AF: 0.859 AC: 4444 AN: 5174

South Asian (SAS) AF: 0.491 AC: 2370 AN: 4824

European-Finnish (FIN) AF: 0.373 AC: 3947 AN: 10570

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21239 AN: 68006

Other (OTH) AF: 0.409 AC: 864 AN: 2112

Alfa AF: 0.354 Hom.: 15571

Bravo AF: 0.402

Asia WGS AF: 0.627 AC: 2176 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 1 (1)
-	-	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	0.068
DANN	Benign	0.41
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8234; hg19: chr11-2870108;