rs41315349

Variant names:

• chr21-34511314-T-C
• rs41315349
• NM_000219.6:c.-375A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-34511314-T-C
• chr21-34511314-T-G

Variant summary

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

The NM_000219.6(KCNE1):​c.-375A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 985,560 control chromosomes in the GnomAD database, including 101 homozygotes. 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 0.016 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: KCNE1 NM_000219.6 splice_region
• Scores: Splicing: ADA: 0.0002495
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.243
• Publications: 2 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000288711 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-34511314-T-C is Benign according to our data. Variant chr21-34511314-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 339782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

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.-375A>G		splice_region	Exon 2 of 4	NP_000210.2
	KCNE1	NM_000219.6	MANE Select	c.-375A>G		5_prime_UTR	Exon 2 of 4	NP_000210.2
	KCNE1	NM_001270402.3		c.-375A>G		5_prime_UTR	Exon 1 of 3	NP_001257331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.-375A>G		splice_region	Exon 2 of 4	ENSP00000382226.2
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.-375A>G		5_prime_UTR	Exon 2 of 4	ENSP00000382226.2
	ENSG00000288711	ENST00000684114.1		n.*171A>G		splice_region non_coding_transcript_exon	Exon 5 of 5	ENSP00000507841.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2496 AN: 152210 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00142 AC: 1181 AN: 833232 Hom.: 35 Cov.: 30 AF XY: 0.00128 AC XY: 493 AN XY: 384808

African (AFR) AF: 0.0642 AC: 1013 AN: 15784

American (AMR) AF: 0.00203 AC: 2 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5152

East Asian (EAS) AF: 0.00 AC: 0 AN: 3636

South Asian (SAS) AF: 0.000122 AC: 2 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 280

Middle Eastern (MID) AF: 0.00432 AC: 7 AN: 1620

European-Non Finnish (NFE) AF: 0.0000932 AC: 71 AN: 762006

Other (OTH) AF: 0.00315 AC: 86 AN: 27308

GnomAD4 genome AF: 0.0164 AC: 2495 AN: 152328 Hom.: 66 Cov.: 33 AF XY: 0.0155 AC XY: 1156 AN XY: 74490

African (AFR) AF: 0.0571 AC: 2375 AN: 41566

American (AMR) AF: 0.00477 AC: 73 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0135 Hom.: 12

Bravo AF: 0.0185

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital long QT syndrome (1)
-	-	1	Jervell and Lange-Nielsen syndrome 2 (1)
-	-	1	Long QT syndrome 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.80
PhyloP100		-0.24
PromoterAI		-0.081	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.042

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

Other links and lift over

dbSNP: rs41315349; hg19: chr21-35883612;