chr7-128767473-G-C

Variant names:

• chr7-128767473-G-C
• rs1240643484
• NM_001219.5:c.661G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001219.5(CALU):​c.661G>C​(p.Asp221His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,316 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CALU NM_001219.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23609865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALU	NM_001219.5	c.661G>C	p.Asp221His	missense_variant	Exon 6 of 7	ENST00000249364.9	NP_001210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALU	ENST00000249364.9	c.661G>C	p.Asp221His	missense_variant	Exon 6 of 7	1	NM_001219.5	ENSP00000249364.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726980

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685G>C (p.D229H) alteration is located in exon 7 (coding exon 6) of the CALU gene. This alteration results from a G to C substitution at nucleotide position 685, causing the aspartic acid (D) at amino acid position 229 to be replaced by a histidine (H). 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	Benign	-0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	.;L;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.83	.;P;.;.
Vest4		0.36
MutPred		0.34		.;Gain of phosphorylation at Y218 (P = 0.09);Gain of phosphorylation at Y218 (P = 0.09);.;
MVP		0.68
MPC		0.91
ClinPred		0.95	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.64

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: rs1240643484; hg19: chr7-128407527;