8-90065899-A-G

Position:

chr8-90065899-A-G

Variant summary

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

The NM_004929.4(CALB1):c.449T>C(p.Met150Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000188 in 1,599,678 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CALB1
NM_004929.4 missense, splice_region

Scores

Splicing: ADA: 0.1590

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51

Variant links:

Genes affected

CALB1 (HGNC:1434): (calbindin 1) The protein encoded by this gene is a member of the calcium-binding protein superfamily that includes calmodulin and troponin C. Originally described as a 27 kDa protein, it is now known to be a 28 kDa protein. It contains four active calcium-binding domains, and has two modified domains that are thought to have lost their calcium binding capability. This protein is thought to buffer entry of calcium upon stimulation of glutamate receptors. Depletion of this protein was noted in patients with Huntington disease. [provided by RefSeq, Jan 2015]

CALB1 links:

LOC124901976 (HGNC:):

LOC124901976 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CALB1	NM_004929.4 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant, splice_region_variant	6/11	ENST00000265431.7	NP_004920.1
LOC124901976	XR_007061004.1 linkuse as main transcript	n.67-140A>G		intron_variant, non_coding_transcript_variant
CALB1	NM_001366795.1 linkuse as main transcript	c.374T>C	p.Met125Thr	missense_variant, splice_region_variant	5/10		NP_001353724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALB1	ENST00000265431.7 linkuse as main transcript	c.449T>C	p.Met150Thr	missense_variant, splice_region_variant	6/11	1	NM_004929.4	ENSP00000265431	P1	P05937-1
CALB1	ENST00000518457.5 linkuse as main transcript	c.278T>C	p.Met93Thr	missense_variant, splice_region_variant	5/10	2		ENSP00000429602		P05937-2
CALB1	ENST00000523716.5 linkuse as main transcript	c.278T>C	p.Met93Thr	missense_variant, splice_region_variant	6/8	2		ENSP00000429246
CALB1	ENST00000520613.5 linkuse as main transcript	c.278T>C	p.Met93Thr	missense_variant, splice_region_variant	7/8	5		ENSP00000430281

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250552

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135472

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447754

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721074

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.449T>C (p.M150T) alteration is located in exon 6 (coding exon 6) of the CALB1 gene. This alteration results from a T to C substitution at nucleotide position 449, causing the methionine (M) at amino acid position 150 to be replaced by a threonine (T). 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

Pathogenic

0.62

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

D;.;.;T

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.5

L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.023

D;T;T;T

Sift4G

Uncertain

0.051

T;D;T;D

Polyphen

0.0080

B;.;.;.

Vest4

0.60

MutPred

0.65

Loss of stability (P = 0.0512);.;.;.;

MVP

0.62

MPC

0.65

ClinPred

0.38

GERP RS

6.0

Varity_R

0.66

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over