7-128759009-A-G

Variant names:

• chr7-128759009-A-G
• rs777311637
• NM_001219.5:c.554A>G

Variant summary

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

The NM_001219.5(CALU):​c.554A>G​(p.Tyr185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (1 hom.)
• Consequence: CALU NM_001219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

Genes affected

CALU (HGNC:1458): (calumenin) The product of this gene is a calcium-binding protein localized in the endoplasmic reticulum (ER) and it is involved in such ER functions as protein folding and sorting. This protein belongs to a family of multiple EF-hand proteins (CERC) that include reticulocalbin, ERC-55, and Cab45 and the product of this gene. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

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=0.38591826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALU	NM_001219.5	c.554A>G	p.Tyr185Cys	missense_variant	Exon 4 of 7	ENST00000249364.9	NP_001210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALU	ENST00000249364.9	c.554A>G	p.Tyr185Cys	missense_variant	Exon 4 of 7	1	NM_001219.5	ENSP00000249364.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 250944 Hom.: 1 AF XY: 0.000103 AC XY: 14 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461620 Hom.: 1 Cov.: 30 AF XY: 0.0000495 AC XY: 36 AN XY: 727118

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: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578A>G (p.Y193C) alteration is located in exon 5 (coding exon 4) of the CALU gene. This alteration results from a A to G substitution at nucleotide position 578, causing the tyrosine (Y) at amino acid position 193 to be replaced by a cysteine (C). 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	0.45
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.6	L;.;L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.044	D;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.91	.;.;P;.;.
Vest4		0.63
MutPred		0.38		Loss of phosphorylation at Y185 (P = 0.0171);.;Loss of phosphorylation at Y185 (P = 0.0171);Loss of phosphorylation at Y185 (P = 0.0171);.;
MVP		0.84
MPC		1.2
ClinPred		0.25	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs777311637; hg19: chr7-128399063;