2-187383279-C-G

Variant names:

• chr2-187383279-C-G
• NM_005795.6:c.78G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005795.6(CALCRL):​c.78G>C​(p.Glu26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALCRL NM_005795.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.510
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050148517).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCRL	NM_005795.6	MANE Select	c.78G>C	p.Glu26Asp	missense	Exon 5 of 15	NP_005786.1	Q16602
	CALCRL	NM_001271751.2		c.78G>C	p.Glu26Asp	missense	Exon 4 of 14	NP_001258680.1	Q16602
	CALCRL	NM_001369434.1		c.78G>C	p.Glu26Asp	missense	Exon 6 of 16	NP_001356363.1	Q16602

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCRL	ENST00000392370.8	TSL:1 MANE Select	c.78G>C	p.Glu26Asp	missense	Exon 5 of 15	ENSP00000376177.3	Q16602
	CALCRL	ENST00000409998.5	TSL:5	c.78G>C	p.Glu26Asp	missense	Exon 6 of 16	ENSP00000386972.1	Q16602
	CALCRL	ENST00000410068.5	TSL:2	c.78G>C	p.Glu26Asp	missense	Exon 4 of 14	ENSP00000387190.1	Q16602

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.8
DANN	Benign	0.94
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.51
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.029
Sift	Benign	0.51	T
Sift4G	Benign	0.61	T
Vest4		0.15
MutPred		0.25		Loss of glycosylation at P28 (P = 0.0864)
MVP		0.43
MPC		0.43
ClinPred		0.11	T
GERP RS		-0.77
gMVP		0.49
Mutation Taster		=91/9	polymorphism

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

hg19: chr2-188248006;