chr21-34511192-T-C

Variant names:

• chr21-34511192-T-C
• rs41315471
• NM_000219.6:c.-253A>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.-253A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 985,752 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (127 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (75 hom.)
• Consequence: KCNE1 NM_000219.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.244
• Publications: 1 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

ENSG00000288711 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 21-34511192-T-C is Benign according to our data. Variant chr21-34511192-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 339780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.071 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.-253A>G		5_prime_UTR	Exon 2 of 4	NP_000210.2	P15382
	KCNE1	NM_001270402.3		c.-253A>G		5_prime_UTR	Exon 1 of 3	NP_001257331.1	C7S316
	KCNE1	NM_001270403.2		c.-225A>G		5_prime_UTR	Exon 1 of 3	NP_001257332.1	P15382

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.-253A>G		5_prime_UTR	Exon 2 of 4	ENSP00000382226.2	P15382
	ENSG00000288711	ENST00000684114.1		n.*293A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000507841.1	A0A804HKA1
	ENSG00000288711	ENST00000684114.1		n.*293A>G		3_prime_UTR	Exon 5 of 5	ENSP00000507841.1	A0A804HKA1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3787 AN: 152174 Hom.: 126 Cov.: 33

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0452

Gnomad SAS AF: 0.0460

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00326 AC: 2718 AN: 833460 Hom.: 75 Cov.: 30 AF XY: 0.00317 AC XY: 1220 AN XY: 384966

African (AFR) AF: 0.0821 AC: 1297 AN: 15792

American (AMR) AF: 0.00610 AC: 6 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5156

East Asian (EAS) AF: 0.0519 AC: 189 AN: 3642

South Asian (SAS) AF: 0.0428 AC: 705 AN: 16466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 278

Middle Eastern (MID) AF: 0.00985 AC: 16 AN: 1624

European-Non Finnish (NFE) AF: 0.000255 AC: 194 AN: 762200

Other (OTH) AF: 0.0114 AC: 311 AN: 27318

GnomAD4 genome AF: 0.0249 AC: 3799 AN: 152292 Hom.: 127 Cov.: 33 AF XY: 0.0256 AC XY: 1906 AN XY: 74462

African (AFR) AF: 0.0732 AC: 3042 AN: 41566

American (AMR) AF: 0.0127 AC: 194 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0448 AC: 232 AN: 5182

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68016

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.0323 Hom.: 73

Bravo AF: 0.0275

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.9
DANN	Benign	0.61
PhyloP100		0.24
PromoterAI		-0.0032	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41315471; hg19: chr21-35883490;