NM_005795.6:c.254T>C

Variant names:

• chr2-187380718-A-G
• rs1039696766
• NM_005795.6:c.254T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005795.6(CALCRL):​c.254T>C​(p.Met85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CALCRL NM_005795.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16481143).

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.254T>C	p.Met85Thr	missense	Exon 6 of 15	NP_005786.1	Q16602
	CALCRL	NM_001271751.2		c.254T>C	p.Met85Thr	missense	Exon 5 of 14	NP_001258680.1	Q16602
	CALCRL	NM_001369434.1		c.254T>C	p.Met85Thr	missense	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.254T>C	p.Met85Thr	missense	Exon 6 of 15	ENSP00000376177.3	Q16602
	CALCRL	ENST00000409998.5	TSL:5	c.254T>C	p.Met85Thr	missense	Exon 7 of 16	ENSP00000386972.1	Q16602
	CALCRL	ENST00000410068.5	TSL:2	c.254T>C	p.Met85Thr	missense	Exon 5 of 14	ENSP00000387190.1	Q16602

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251410 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

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	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.89
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.055
Sift	Benign	0.34	T
Sift4G	Benign	0.38	T
Vest4		0.32
MutPred		0.28		Gain of glycosylation at S84 (P = 0.0648)
MVP		0.38
MPC		0.55
ClinPred		0.14	T
GERP RS		5.4
gMVP		0.64
Mutation Taster		=47/53	disease causing

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: rs1039696766; hg19: chr2-188245445;