13-49377005-C-A

Variant names:

• chr13-49377005-C-A
• rs1160064033
• NM_001079670.3:c.238G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079670.3(CAB39L):​c.238G>T​(p.Val80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAB39L NM_001079670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• Publications: 0 publications found

Genes affected

CAB39L (HGNC:20290): (calcium binding protein 39 like) Predicted to enable protein serine/threonine kinase activator activity. Predicted to be involved in intracellular signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000297916 (HGNC:):

ACMG classification

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=0.13504475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAB39L	NM_001079670.3	c.238G>T	p.Val80Leu	missense_variant	Exon 5 of 11	ENST00000409308.6	NP_001073138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAB39L	ENST00000409308.6	c.238G>T	p.Val80Leu	missense_variant	Exon 5 of 11	1	NM_001079670.3	ENSP00000386375.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251166 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460792 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726742

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

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111254

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238G>T (p.V80L) alteration is located in exon 3 (coding exon 2) of the CAB39L gene. This alteration results from a G to T substitution at nucleotide position 238, causing the valine (V) at amino acid position 80 to be replaced by a leucine (L). 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	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.038	T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	.;.;T;.;T;.;T;D;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.74	N;N;N;N;.;N;.;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.16	N;.;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.66	T;.;T;T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T;.;.;.
Polyphen		0.0	B;B;B;B;.;B;.;.;.
Vest4		0.20
MutPred		0.35		Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);.;Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);Loss of catalytic residue at V80 (P = 0.0648);
MVP		0.29
MPC		0.15
ClinPred		0.25	T
GERP RS		5.5
PromoterAI		-0.0092	Neutral
Varity_R		0.22
gMVP		0.20
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs1160064033; hg19: chr13-49951141;