2-187352176-G-T

Position:

• chr2-187352176-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005795.6(CALCRL):​c.1066C>A​(p.Pro356Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 9.98

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALCRL	NM_005795.6	c.1066C>A	p.Pro356Thr	missense_variant	13/15	ENST00000392370.8	NP_005786.1
CALCRL-AS1	XR_007087504.1	n.3420-147330G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALCRL	ENST00000392370.8	c.1066C>A	p.Pro356Thr	missense_variant	13/15	1	NM_005795.6	ENSP00000376177	P1
CALCRL-AS1	ENST00000412276.6	n.190-147330G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.1066C>A (p.P356T) alteration is located in exon 13 (coding exon 10) of the CALCRL gene. This alteration results from a C to A substitution at nucleotide position 1066, causing the proline (P) at amino acid position 356 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Vest4		0.87
MutPred		0.84		Loss of ubiquitination at K359 (P = 0.069);Loss of ubiquitination at K359 (P = 0.069);Loss of ubiquitination at K359 (P = 0.069);
MVP		0.93
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-188216903;