rs2277382

chr12-51912437-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000550683.5(ACVRL1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,611,008 control chromosomes in the GnomAD database, including 5,581 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (488 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5093 hom.)
• Consequence: ACVRL1 ENST00000550683.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.272

Genes affected

ACVRL1 (HGNC:175): (activin A receptor like type 1) This gene encodes a type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases. Mutations in this gene are associated with hemorrhagic telangiectasia type 2, also known as Rendu-Osler-Weber syndrome 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACVRL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0028590858).
• BP6: Variant 12-51912437-C-T is Benign according to our data. Variant chr12-51912437-C-T is described in ClinVar as [Benign]. Clinvar id is 136292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51912437-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVRL1	NM_000020.3	c.-5-33C>T		intron_variant		ENST00000388922.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVRL1	ENST00000388922.9	c.-5-33C>T		intron_variant		1	NM_000020.3	P1

Frequencies

GnomAD3 genomes AF: 0.0770 AC: 11709 AN: 152122 Hom.: 487 Cov.: 32

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.0943

Gnomad EAS AF: 0.0942

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.0955

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0803

GnomAD3 exomes AF: 0.0838 AC: 21002 AN: 250560 Hom.: 938 AF XY: 0.0823 AC XY: 11158 AN XY: 135504

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.0959

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0788

Gnomad SAS exome AF: 0.0571

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.0825

GnomAD4 exome AF: 0.0815 AC: 118853 AN: 1458768 Hom.: 5093 Cov.: 32 AF XY: 0.0808 AC XY: 58625 AN XY: 725826

Gnomad4 AFR exome AF: 0.0627

Gnomad4 AMR exome AF: 0.0919

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.0595

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.0808

Gnomad4 OTH exome AF: 0.0787

GnomAD4 genome AF: 0.0769 AC: 11710 AN: 152240 Hom.: 488 Cov.: 32 AF XY: 0.0764 AC XY: 5687 AN XY: 74430

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.0802

Gnomad4 ASJ AF: 0.0943

Gnomad4 EAS AF: 0.0942

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.0955

Gnomad4 NFE AF: 0.0817

Gnomad4 OTH AF: 0.0804

Alfa AF: 0.0777 Hom.: 105

Bravo AF: 0.0768

TwinsUK AF: 0.0809 AC: 300

ALSPAC AF: 0.0781 AC: 301

ESP6500AA AF: 0.0608 AC: 268

ESP6500EA AF: 0.0841 AC: 723

ExAC AF: 0.0830 AC: 10074

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.0872

EpiControl AF: 0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	3.3
Dann	Benign	0.88
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D
Polyphen		0.0	.;.;B
Vest4		0.024, 0.094
ClinPred		0.0041	T
GERP RS		-6.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2277382; hg19: chr12-52306221;