10-133328015-C-T

Position:

• chr10-133328015-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001321617.2(CALY):​c.-271G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000556 in 1,595,858 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (2 hom.)
• Consequence: CALY NM_001321617.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9719
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.415

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:38088): (ZNF511-PRAP1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ZNF511 (zinc finger protein 511) and PRAP1 (proline-rich acidic protein 1) genes on chromosome 10. The putative readthrough transcript may encode a fusion protein that shares sequence identity with each individual gene product and may be involved in the regulation of gene promoters, particularly those found on transfected plasmids. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07680413).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALY	NM_015722.4	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/6	ENST00000252939.9	NP_056537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALY	ENST00000252939.9	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/6	1	NM_015722.4	ENSP00000252939.4
ZNF511-PRAP1	ENST00000368554.8	c.506+16174C>T		intron_variant		2		ENSP00000357542.5
CALY	ENST00000368555.3	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/3	2		ENSP00000357543.3
CALY	ENST00000368558.1	c.136G>A	p.Val46Met	missense_variant, splice_region_variant	3/5	5		ENSP00000357546.1

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 99 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000574 AC: 136 AN: 236790 Hom.: 1 AF XY: 0.000593 AC XY: 76 AN XY: 128250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000390

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000277

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000547 AC: 789 AN: 1443534 Hom.: 2 Cov.: 26 AF XY: 0.000589 AC XY: 423 AN XY: 718260

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000341

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.000531

Gnomad4 NFE exome AF: 0.000641

Gnomad4 OTH exome AF: 0.000285

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74490

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000879 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000603 AC: 73

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

Mar 16, 2022

The c.136G>A (p.V46M) alteration is located in exon 3 (coding exon 2) of the CALY gene. This alteration results from a G to A substitution at nucleotide position 136, causing the valine (V) at amino acid position 46 to be replaced by a methionine (M). 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	0.25
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T;T;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.32
MVP		0.26
MPC		0.99
ClinPred		0.075	T
GERP RS		4.3
Varity_R		0.53
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.56
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

LitVar

Other links and lift over

dbSNP: rs142408423; hg19: chr10-135141519;