8-90063143-A-G

Position:

• chr8-90063143-A-G

Variant summary

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

The NM_004929.4(CALB1):​c.557T>C​(p.Met186Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALB1 NM_004929.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

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]

LOC124901976 (HGNC:):

ACMG classification

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	UniProt
CALB1	NM_004929.4	c.557T>C	p.Met186Thr	missense_variant	9/11	ENST00000265431.7	NP_004920.1
LOC124901976	XR_007061004.1	n.66+1887A>G		intron_variant, non_coding_transcript_variant
CALB1	NM_001366795.1	c.482T>C	p.Met161Thr	missense_variant	8/10		NP_001353724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALB1	ENST00000265431.7	c.557T>C	p.Met186Thr	missense_variant	9/11	1	NM_004929.4	ENSP00000265431	P1
CALB1	ENST00000518457.5	c.386T>C	p.Met129Thr	missense_variant	8/10	2		ENSP00000429602
CALB1	ENST00000469032.1	n.1199T>C		non_coding_transcript_exon_variant	2/3	2
CALB1	ENST00000522070.1	n.76T>C		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.557T>C (p.M186T) alteration is located in exon 9 (coding exon 9) of the CALB1 gene. This alteration results from a T to C substitution at nucleotide position 557, causing the methionine (M) at amino acid position 186 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	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.94	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.34	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.90	P;.
Vest4		0.87
MutPred		0.47		Gain of phosphorylation at M186 (P = 0.1256);.;
MVP		0.90
MPC		1.5
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-91075371;