chr21-34449972-T-C

Variant names:

• chr21-34449972-T-C
• rs2070358
• NM_000219.6:c.-50-288A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000219.6(KCNE1):​c.-50-288A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.014 (31 hom., cov: 12)
• Consequence: KCNE1 NM_000219.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.46
• Publications: 12 publications found

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-34449972-T-C is Benign according to our data. Variant chr21-34449972-T-C is described in ClinVar as Benign. ClinVar VariationId is 675606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	NM_000219.6	MANE Select	c.-50-288A>G		intron	N/A	NP_000210.2	P15382
	KCNE1	NM_001127668.4		c.-50-288A>G		intron	N/A	NP_001121140.1	P15382
	KCNE1	NM_001127669.4		c.-50-288A>G		intron	N/A	NP_001121141.1	C7S316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.-50-288A>G		intron	N/A	ENSP00000382226.2	P15382
	KCNE1	ENST00000399289.7	TSL:1	c.-50-288A>G		intron	N/A	ENSP00000382228.3	P15382
	KCNE1	ENST00000416357.6	TSL:1	c.-50-288A>G		intron	N/A	ENSP00000416258.2	P15382

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 1105 AN: 78956 Hom.: 31 Cov.: 12

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.00356

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0131

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0140 AC: 1109 AN: 79036 Hom.: 31 Cov.: 12 AF XY: 0.0138 AC XY: 531 AN XY: 38366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00860 AC: 194 AN: 22552

American (AMR) AF: 0.0139 AC: 119 AN: 8582

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 25 AN: 1780

East Asian (EAS) AF: 0.0263 AC: 47 AN: 1784

South Asian (SAS) AF: 0.0255 AC: 61 AN: 2392

European-Finnish (FIN) AF: 0.0176 AC: 99 AN: 5612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.0159 AC: 548 AN: 34544

Other (OTH) AF: 0.0130 AC: 14 AN: 1074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.597 Hom.: 46876

Asia WGS AF: 0.590 AC: 2056 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.43
PhyloP100		-2.5
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: rs2070358; hg19: chr21-35822270;