NM_005795.6:c.187G>A

Variant names:

• chr2-187380785-C-T
• rs757975393
• NM_005795.6:c.187G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_005795.6(CALCRL):​c.187G>A​(p.Val63Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,458,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CALCRL NM_005795.6 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.404
• 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=0.079672605).
• BP6: Variant 2-187380785-C-T is Benign according to our data. Variant chr2-187380785-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3136668.Status of the report is criteria_provided_single_submitter, 1 stars.

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.187G>A	p.Val63Ile	missense splice_region	Exon 6 of 15	NP_005786.1	Q16602
	CALCRL	NM_001271751.2		c.187G>A	p.Val63Ile	missense splice_region	Exon 5 of 14	NP_001258680.1	Q16602
	CALCRL	NM_001369434.1		c.187G>A	p.Val63Ile	missense splice_region	Exon 7 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.187G>A	p.Val63Ile	missense splice_region	Exon 6 of 15	ENSP00000376177.3	Q16602
	CALCRL	ENST00000409998.5	TSL:5	c.187G>A	p.Val63Ile	missense splice_region	Exon 7 of 16	ENSP00000386972.1	Q16602
	CALCRL	ENST00000410068.5	TSL:2	c.187G>A	p.Val63Ile	missense splice_region	Exon 5 of 14	ENSP00000387190.1	Q16602

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000480 AC: 12 AN: 250000 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1458706 Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14 AN XY: 725820

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.000134 AC: 6 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39654

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1109348

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.059
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.8
DANN	Benign	0.86
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.40
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.072
Sift	Benign	0.62	T
Sift4G	Benign	0.33	T
Vest4		0.085
MutPred		0.44		Gain of loop (P = 0.4248)
MVP		0.26
MPC		0.38
ClinPred		0.018	T
GERP RS		-1.8
gMVP		0.38
Mutation Taster		=84/16	polymorphism

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: rs757975393; hg19: chr2-188245512;