16-71383379-G-C

Position:

• chr16-71383379-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001740.5(CALB2):​c.412G>C​(p.Asp138His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALB2 NM_001740.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

Genes affected

CALB2 (HGNC:1435): (calbindin 2) This gene encodes an intracellular calcium-binding protein belonging to the troponin C superfamily. Members of this protein family have six EF-hand domains which bind calcium. This protein plays a role in diverse cellular functions, including message targeting and intracellular calcium buffering. It also functions as a modulator of neuronal excitability, and is a diagnostic marker for some human diseases, including Hirschsprung disease and some cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]

CALB2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALB2	NM_001740.5	c.412G>C	p.Asp138His	missense_variant	6/11	ENST00000302628.9	NP_001731.2
CALB2	NM_007088.4	c.412G>C	p.Asp138His	missense_variant	6/9		NP_009019.1
CALB2	NR_027910.3	n.482G>C		non_coding_transcript_exon_variant	6/10
LOC105371332	XR_933714.3	n.224+231C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALB2	ENST00000302628.9	c.412G>C	p.Asp138His	missense_variant	6/11	1	NM_001740.5	ENSP00000307508.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 08, 2022

The c.412G>C (p.D138H) alteration is located in exon 6 (coding exon 6) of the CALB2 gene. This alteration results from a G to C substitution at nucleotide position 412, causing the aspartic acid (D) at amino acid position 138 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.10	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.95	P;B
Vest4		0.94
MutPred		0.71		Loss of ubiquitination at K133 (P = 0.0563);Loss of ubiquitination at K133 (P = 0.0563);
MVP		0.90
MPC		0.40
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-71417282;