10-133328970-C-A

Variant summary

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

The NM_015722.4(CALY):c.20G>T(p.Ser7Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,536 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: 7.1e-7 (0 hom.)
• Consequence: CALY NM_015722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0710

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=0.3469979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALY	NM_015722.4	c.20G>T	p.Ser7Ile	missense_variant	2/6	ENST00000252939.9
ZNF511-PRAP1	NM_001396060.1	c.680+17129C>A		intron_variant
CALY	NM_001321617.2	c.-387G>T		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALY	ENST00000252939.9	c.20G>T	p.Ser7Ile	missense_variant	2/6	1	NM_015722.4	P1
CALY	ENST00000368555.3	c.20G>T	p.Ser7Ile	missense_variant	2/3	2
CALY	ENST00000368558.1	c.20G>T	p.Ser7Ile	missense_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412536 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 10, 2022

The c.20G>T (p.S7I) alteration is located in exon 2 (coding exon 1) of the CALY gene. This alteration results from a G to T substitution at nucleotide position 20, causing the serine (S) at amino acid position 7 to be replaced by an isoleucine (I). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	T;T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	0.68	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.29
MutPred		0.55		Loss of phosphorylation at S7 (P = 0.0437);Loss of phosphorylation at S7 (P = 0.0437);Loss of phosphorylation at S7 (P = 0.0437);
MVP		0.27
MPC		1.5
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs866303467; hg19: chr10-135142474;