Genetic Variant CALU:p.Thr4Asn (chr7-128748365-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001199671.2(CALU):c.11C>A(p.Thr4Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

CALU
NM_001199671.2 missense, splice_region

Scores

Splicing: ADA: 0.0001769

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.613

Publications

0 publications found

Variant links:

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]

CALU links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10813853).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199671.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALU	NM_001219.5	MANE Select	c.-11-208C>A		intron	N/A	NP_001210.1	Q6IAW5
CALU	NM_001199671.2		c.11C>A	p.Thr4Asn	missense splice_region	Exon 2 of 8	NP_001186600.1	O43852-3
CALU	NM_001199672.2		c.11C>A	p.Thr4Asn	missense splice_region	Exon 2 of 8	NP_001186601.1	O43852-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALU	ENST00000479257.5	TSL:1	c.11C>A	p.Thr4Asn	missense splice_region	Exon 2 of 8	ENSP00000420381.1	O43852-3
CALU	ENST00000542996.7	TSL:1	c.11C>A	p.Thr4Asn	missense splice_region	Exon 2 of 8	ENSP00000438248.1	O43852-4
CALU	ENST00000249364.9	TSL:1 MANE Select	c.-11-208C>A		intron	N/A	ENSP00000249364.4	O43852-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.41e-7

AC:

AN:

1349608

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666694

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30492

American (AMR)

AF:

0.00

AC:

AN:

32716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24630

East Asian (EAS)

AF:

0.00

AC:

AN:

35500

South Asian (SAS)

AF:

0.00

AC:

AN:

74548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

9.47e-7

AC:

AN:

1055608

Other (OTH)

AF:

0.00

AC:

AN:

56722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.86

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.49

M_CAP

Benign

0.0030

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

-0.61

PROVEAN

Benign

-0.24

REVEL

Benign

0.043

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.14

MutPred

0.22

Gain of ubiquitination at K2 (P = 0.0577)

MVP

0.54

MPC

0.37

ClinPred

0.035

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.33

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.018

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over