rs12562197

Variant names:

• chr1-21245108-G-A
• rs12562197
• NM_001397.3:c.1164-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21245108-G-A
• chr1-21245108-G-C

Variant summary

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

The NM_001397.3(ECE1):​c.1164-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,612,490 control chromosomes in the GnomAD database, including 57,766 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4204 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53562 hom.)
• Consequence: ECE1 NM_001397.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001958
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00100

Genes affected

ECE1 (HGNC:3146): (endothelin converting enzyme 1) The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-21245108-G-A is Benign according to our data. Variant chr1-21245108-G-A is described in ClinVar as [Benign]. Clinvar id is 258081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECE1	NM_001397.3	c.1164-5C>T		splice_region_variant, intron_variant	Intron 9 of 18	ENST00000374893.11	NP_001388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECE1	ENST00000374893.11	c.1164-5C>T		splice_region_variant, intron_variant	Intron 9 of 18	1	NM_001397.3	ENSP00000364028.6

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32097 AN: 152026 Hom.: 4207 Cov.: 32

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.236 AC: 59041 AN: 250150 AF XY: 0.240

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.266 AC: 387964 AN: 1460346 Hom.: 53562 Cov.: 33 AF XY: 0.264 AC XY: 191880 AN XY: 726528

Gnomad4 AFR exome AF: 0.0584 AC: 1952 AN: 33452

Gnomad4 AMR exome AF: 0.217 AC: 9702 AN: 44616

Gnomad4 ASJ exome AF: 0.209 AC: 5457 AN: 26124

Gnomad4 EAS exome AF: 0.139 AC: 5515 AN: 39682

Gnomad4 SAS exome AF: 0.205 AC: 17684 AN: 86202

Gnomad4 FIN exome AF: 0.298 AC: 15887 AN: 53324

Gnomad4 NFE exome AF: 0.284 AC: 315868 AN: 1110876

Gnomad4 Remaining exome AF: 0.241 AC: 14522 AN: 60326

GnomAD4 genome AF: 0.211 AC: 32100 AN: 152144 Hom.: 4204 Cov.: 32 AF XY: 0.209 AC XY: 15582 AN XY: 74390

Gnomad4 AFR AF: 0.0637 AC: 0.0636582 AN: 0.0636582

Gnomad4 AMR AF: 0.247 AC: 0.246822 AN: 0.246822

Gnomad4 ASJ AF: 0.198 AC: 0.198037 AN: 0.198037

Gnomad4 EAS AF: 0.131 AC: 0.130897 AN: 0.130897

Gnomad4 SAS AF: 0.190 AC: 0.189519 AN: 0.189519

Gnomad4 FIN AF: 0.310 AC: 0.309834 AN: 0.309834

Gnomad4 NFE AF: 0.285 AC: 0.285027 AN: 0.285027

Gnomad4 OTH AF: 0.219 AC: 0.218898 AN: 0.218898

Alfa AF: 0.253 Hom.: 19014

Bravo AF: 0.199

Asia WGS AF: 0.154 AC: 539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs12562197; hg19: chr1-21571601; COSMIC: COSV51662497;