10-133328973-C-T

Variant summary

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

The NM_015722.4(CALY):c.17G>A(p.Cys6Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,412,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CALY NM_015722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.944

Genes affected

CALY (HGNC:17938): (calcyon neuron specific vesicular protein) The protein encoded by this gene is a type II single transmembrane protein. It is required for maximal stimulated calcium release after stimulation of purinergic or muscarinic but not beta-adrenergic receptors. The encoded protein interacts with D1 dopamine receptor and may interact with other DA receptor subtypes and/or GPCRs. [provided by RefSeq, Jul 2008]

ZNF511-PRAP1 (HGNC:):

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=0.29042011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALY	NM_015722.4	c.17G>A	p.Cys6Tyr	missense_variant	2/6	ENST00000252939.9
ZNF511-PRAP1	NM_001396060.1	c.680+17132C>T		intron_variant
CALY	NM_001321617.2	c.-390G>A		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALY	ENST00000252939.9	c.17G>A	p.Cys6Tyr	missense_variant	2/6	1	NM_015722.4	P1
CALY	ENST00000368555.3	c.17G>A	p.Cys6Tyr	missense_variant	2/3	2
CALY	ENST00000368558.1	c.17G>A	p.Cys6Tyr	missense_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1412062 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Aug 13, 2021

The c.17G>A (p.C6Y) alteration is located in exon 2 (coding exon 1) of the CALY gene. This alteration results from a G to A substitution at nucleotide position 17, causing the cysteine (C) at amino acid position 6 to be replaced by a tyrosine (Y). 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	0.26
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	0.86	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.23
Sift	Benign	0.065	T;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.28
MutPred		0.56		Gain of phosphorylation at C6 (P = 0.0269);Gain of phosphorylation at C6 (P = 0.0269);Gain of phosphorylation at C6 (P = 0.0269);
MVP		0.50
MPC		1.7
ClinPred		0.69	D
GERP RS		3.5
Varity_R		0.36
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1485887393; hg19: chr10-135142477;