7-93426555-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001742.4(CALCR):c.1226T>C(p.Phe409Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 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)
• Consequence: CALCR NM_001742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.878

Genes affected

CALCR (HGNC:1440): (calcitonin receptor) This gene encodes a high affinity receptor for the peptide hormone calcitonin and belongs to a subfamily of seven transmembrane-spanning G protein-coupled receptors. The encoded protein is involved in maintaining calcium homeostasis and in regulating osteoclast-mediated bone resorption. Polymorphisms in this gene have been associated with variations in bone mineral density and onset of osteoporosis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2871521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALCR	NM_001742.4	c.1226T>C	p.Phe409Ser	missense_variant	14/14	ENST00000426151.7
CALCR	NM_001164737.3	c.1274T>C	p.Phe425Ser	missense_variant	16/16
CALCR	NM_001164738.2	c.1226T>C	p.Phe409Ser	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALCR	ENST00000426151.7	c.1226T>C	p.Phe409Ser	missense_variant	14/14	1	NM_001742.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 10, 2022

The c.1226T>C (p.F409S) alteration is located in exon 14 (coding exon 12) of the CALCR gene. This alteration results from a T to C substitution at nucleotide position 1226, causing the phenylalanine (F) at amino acid position 409 to be replaced by a serine (S). 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	Benign	0.30
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Uncertain	0.98
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.093	N
LIST_S2	Uncertain	0.90	D;.;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D
REVEL	Benign	0.15
Sift	Uncertain	0.013	D;D;D;.;D
Sift4G	Uncertain	0.024	D;D;D;.;D
Vest4		0.17
MutPred		0.68		.;.;Gain of disorder (P = 0.0436);.;Gain of disorder (P = 0.0436);
MVP		0.79
MPC		0.85
ClinPred		0.54	D
GERP RS		0.80
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-93055867;