2-187352080-T-C

Variant names:

• chr2-187352080-T-C
• rs858745
• NM_005795.6:c.1128+34A>G

Variant summary

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

The NM_005795.6(CALCRL):​c.1128+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,593,056 control chromosomes in the GnomAD database, including 590,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57464 hom., cov: 31)
  • Exomes 𝑓: 0.86 (533185 hom.)
• Consequence: CALCRL NM_005795.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.227
• Publications: 10 publications found

Genes affected

CALCRL (HGNC:16709): (calcitonin receptor like receptor) Enables adrenomedullin binding activity; adrenomedullin receptor activity; and calcitonin gene-related peptide receptor activity. Involved in several processes, including G protein-coupled receptor signaling pathway; cellular response to sucrose stimulus; and receptor internalization. Located in endoplasmic reticulum; endosome; and lysosome. Part of CGRP receptor complex and adrenomedullin receptor complex. Colocalizes with plasma membrane. Implicated in hereditary lymphedema. [provided by Alliance of Genome Resources, Apr 2022]

CALCRL-AS1 (HGNC:55863): (CALCRL and TFPI antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-187352080-T-C is Benign according to our data. Variant chr2-187352080-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005795.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCRL	NM_005795.6	MANE Select	c.1128+34A>G		intron	N/A	NP_005786.1
	CALCRL	NM_001271751.2		c.1128+34A>G		intron	N/A	NP_001258680.1
	CALCRL	NM_001369434.1		c.1128+34A>G		intron	N/A	NP_001356363.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCRL	ENST00000392370.8	TSL:1 MANE Select	c.1128+34A>G		intron	N/A	ENSP00000376177.3
	CALCRL	ENST00000409998.5	TSL:5	c.1128+34A>G		intron	N/A	ENSP00000386972.1
	CALCRL	ENST00000410068.5	TSL:2	c.1128+34A>G		intron	N/A	ENSP00000387190.1

Frequencies

GnomAD3 genomes AF: 0.869 AC: 131662 AN: 151564 Hom.: 57410 Cov.: 31

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.871

GnomAD2 exomes AF: 0.845 AC: 210952 AN: 249514 AF XY: 0.846

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.904

Gnomad EAS exome AF: 0.741

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.855

GnomAD4 exome AF: 0.859 AC: 1238603 AN: 1441374 Hom.: 533185 Cov.: 26 AF XY: 0.858 AC XY: 616247 AN XY: 718290

African (AFR) AF: 0.913 AC: 30085 AN: 32968

American (AMR) AF: 0.794 AC: 35345 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 23444 AN: 25882

East Asian (EAS) AF: 0.753 AC: 29786 AN: 39536

South Asian (SAS) AF: 0.812 AC: 69706 AN: 85842

European-Finnish (FIN) AF: 0.886 AC: 47202 AN: 53304

Middle Eastern (MID) AF: 0.911 AC: 5201 AN: 5706

European-Non Finnish (NFE) AF: 0.865 AC: 946233 AN: 1093988

Other (OTH) AF: 0.865 AC: 51601 AN: 59654

GnomAD4 genome AF: 0.869 AC: 131771 AN: 151682 Hom.: 57464 Cov.: 31 AF XY: 0.867 AC XY: 64241 AN XY: 74124

African (AFR) AF: 0.909 AC: 37670 AN: 41450

American (AMR) AF: 0.817 AC: 12403 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 3157 AN: 3462

East Asian (EAS) AF: 0.751 AC: 3831 AN: 5100

South Asian (SAS) AF: 0.793 AC: 3826 AN: 4824

European-Finnish (FIN) AF: 0.884 AC: 9366 AN: 10598

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58612 AN: 67760

Other (OTH) AF: 0.871 AC: 1837 AN: 2108

Alfa AF: 0.878 Hom.: 12189

Bravo AF: 0.866

Asia WGS AF: 0.789 AC: 2743 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lymphatic malformation 8 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.60
PhyloP100		-0.23
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs858745; hg19: chr2-188216807; COSMIC: COSV66474479;