chr10-133328015-C-T

Variant names:

• chr10-133328015-C-T
• rs142408423
• NM_015722.4:c.136G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321617.2. 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
	CALY	NM_015722.4	MANE Select	c.136G>A	p.Val46Met	missense splice_region	Exon 3 of 6	NP_056537.1	Q9NYX4-1
	CALY	NM_001321617.2		c.-271G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_001308546.1
	CALY	NM_001321617.2		c.-271G>A		splice_region	Exon 3 of 6	NP_001308546.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALY	ENST00000252939.9	TSL:1 MANE Select	c.136G>A	p.Val46Met	missense splice_region	Exon 3 of 6	ENSP00000252939.4	Q9NYX4-1
	ZNF511-PRAP1	ENST00000368554.8	TSL:2	c.506+16174C>T		intron	N/A	ENSP00000357542.5	H7BY64
	CALY	ENST00000956089.1		c.136G>A	p.Val46Met	missense splice_region	Exon 3 of 6	ENSP00000626148.1

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

GnomAD2 exomes AF: 0.000574 AC: 136 AN: 236790 AF XY: 0.000593

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 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

African (AFR) AF: 0.0000302 AC: 1 AN: 33120

American (AMR) AF: 0.000341 AC: 15 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25864

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.000236 AC: 20 AN: 84688

European-Finnish (FIN) AF: 0.000531 AC: 28 AN: 52718

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.000641 AC: 704 AN: 1098244

Other (OTH) AF: 0.000285 AC: 17 AN: 59746

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.000850 AC: 13 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000825 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

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	0.25
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
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.077	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.41
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs142408423; hg19: chr10-135141519; COSMIC: COSV108053789; COSMIC: COSV108053789;