2-187346278-C-A

Variant names:

• chr2-187346278-C-A
• rs148965095
• NM_005795.6:c.1292G>T

Variant summary

Our verdict is Benign. The variant received -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. 15/19 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
• Publications: 3 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 (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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 Unknown gene

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.1292G>T	p.Gly431Val	missense	Exon 15 of 15	NP_005786.1	Q16602
	CALCRL	NM_001271751.2		c.1292G>T	p.Gly431Val	missense	Exon 14 of 14	NP_001258680.1	Q16602
	CALCRL	NM_001369434.1		c.1292G>T	p.Gly431Val	missense	Exon 16 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.1292G>T	p.Gly431Val	missense	Exon 15 of 15	ENSP00000376177.3	Q16602
	CALCRL	ENST00000409998.5	TSL:5	c.1292G>T	p.Gly431Val	missense	Exon 16 of 16	ENSP00000386972.1	Q16602
	CALCRL	ENST00000410068.5	TSL:2	c.1292G>T	p.Gly431Val	missense	Exon 14 of 14	ENSP00000387190.1	Q16602

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

GnomAD2 exomes AF: 0.00924 AC: 2314 AN: 250424 AF XY: 0.00731

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33400

American (AMR) AF: 0.0512 AC: 2280 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0286 AC: 1134 AN: 39662

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111042

Other (OTH) AF: 0.00221 AC: 133 AN: 60314

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

African (AFR) AF: 0.000723 AC: 30 AN: 41496

American (AMR) AF: 0.0330 AC: 502 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0240 AC: 124 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67832

Other (OTH) AF: 0.00714 AC: 15 AN: 2102

Alfa AF: 0.000961 Hom.: 7

Bravo AF: 0.00730

ExAC AF: 0.00719 AC: 873

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.093
Sift	Benign	0.62	T
Sift4G	Benign	0.69	T
Vest4		0.34
MVP		0.50
MPC		0.63
ClinPred		0.013	T
GERP RS		4.8
gMVP		0.67
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs148965095; hg19: chr2-188211005;