2-187346278-C-A

Position:

• chr2-187346278-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005795.6(CALCRL):​c.1292G>T​(p.Gly431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,612,268 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (97 hom.)
• Consequence: CALCRL NM_005795.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.10

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006179005).
• BP6: Variant 2-187346278-C-A is Benign according to our data. Variant chr2-187346278-C-A is described in ClinVar as [Benign]. Clinvar id is 778263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00444 (674/151892) while in subpopulation AMR AF= 0.033 (502/15198). AF 95% confidence interval is 0.0306. There are 13 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALCRL	NM_005795.6	c.1292G>T	p.Gly431Val	missense_variant	15/15	ENST00000392370.8	NP_005786.1
CALCRL-AS1	XR_007087504.1	n.3420-153228C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALCRL	ENST00000392370.8	c.1292G>T	p.Gly431Val	missense_variant	15/15	1	NM_005795.6	ENSP00000376177	P1
CALCRL-AS1	ENST00000412276.6	n.190-153228C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 676 AN: 151774 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00721

GnomAD3 exomes AF: 0.00924 AC: 2314 AN: 250424 Hom.: 62 AF XY: 0.00731 AC XY: 989 AN XY: 135374

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0255

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00245 AC: 3581 AN: 1460376 Hom.: 97 Cov.: 30 AF XY: 0.00216 AC XY: 1571 AN XY: 726504

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0286

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00444 AC: 674 AN: 151892 Hom.: 13 Cov.: 32 AF XY: 0.00497 AC XY: 369 AN XY: 74270

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0240

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00714

Alfa AF: 0.00116 Hom.: 2

Bravo AF: 0.00730

ExAC AF: 0.00719 AC: 873

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.93
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.81	N;N;N
REVEL	Benign	0.093
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.69	T;T;T
Vest4		0.34
MVP		0.50
MPC		0.63
ClinPred		0.013	T
GERP RS		4.8
gMVP		0.67

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: rs148965095; hg19: chr2-188211005;