16-71383443-T-A

Variant names:

• chr16-71383443-T-A
• rs143234572
• NM_001740.5:c.476T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001740.5(CALB2):​c.476T>A​(p.Ile159Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I159T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CALB2 NM_001740.5 missense, splice_region
• Scores: Splicing: ADA: 0.6356
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.98
• Publications: 0 publications found

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]

LINC02136 (HGNC:52995): (long intergenic non-protein coding RNA 2136)

LOC105371332 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001740.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALB2	NM_001740.5	MANE Select	c.476T>A	p.Ile159Lys	missense splice_region	Exon 6 of 11	NP_001731.2	A0A140VK08
	CALB2	NM_007088.4		c.476T>A	p.Ile159Lys	missense splice_region	Exon 6 of 9	NP_009019.1	A6NER6
	CALB2	NR_027910.3		n.546T>A		splice_region non_coding_transcript_exon	Exon 6 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALB2	ENST00000302628.9	TSL:1 MANE Select	c.476T>A	p.Ile159Lys	missense splice_region	Exon 6 of 11	ENSP00000307508.4	P22676
	CALB2	ENST00000870349.1		c.593T>A	p.Ile198Lys	missense splice_region	Exon 7 of 12	ENSP00000540408.1
	CALB2	ENST00000959115.1		c.476T>A	p.Ile159Lys	missense splice_region	Exon 6 of 11	ENSP00000629174.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.96	D
Vest4		0.96
MutPred		0.80		Gain of disorder (P = 0.0013)
MVP		0.98
MPC		0.88
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.64
dbscSNV1_RF	Benign	0.55
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

Other links and lift over

dbSNP: rs143234572; hg19: chr16-71417346;