13-49350886-C-T

Variant names:

• chr13-49350886-C-T
• rs149022536
• NM_001079670.3:c.422G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001079670.3(CAB39L):​c.422G>A​(p.Arg141His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,600,274 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (2 hom.)
• Consequence: CAB39L NM_001079670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• Publications: 8 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.079282224).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAB39L	NM_001079670.3	c.422G>A	p.Arg141His	missense_variant	Exon 7 of 11	ENST00000409308.6	NP_001073138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAB39L	ENST00000409308.6	c.422G>A	p.Arg141His	missense_variant	Exon 7 of 11	1	NM_001079670.3	ENSP00000386375.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000332 AC: 8 AN: 240968 AF XY: 0.0000307

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000631

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000608 AC: 88 AN: 1448130 Hom.: 2 Cov.: 30 AF XY: 0.0000611 AC XY: 44 AN XY: 719558

African (AFR) AF: 0.00 AC: 0 AN: 32886

American (AMR) AF: 0.0000474 AC: 2 AN: 42164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 83138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000759 AC: 84 AN: 1106058

Other (OTH) AF: 0.0000167 AC: 1 AN: 59826

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74302

African (AFR) AF: 0.0000483 AC: 2 AN: 41430

American (AMR) AF: 0.000131 AC: 2 AN: 15272

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000790 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422G>A (p.R141H) alteration is located in exon 5 (coding exon 4) of the CAB39L gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 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	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T;T;T;T;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	.;.;D;.;D;.;D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.079	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N;N;N;N;.;N;.
PhyloP100		2.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.36	N;.;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.49	T;.;T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;.
Polyphen		0.0040	B;B;B;B;.;B;.
Vest4		0.35
MVP		0.24
MPC		0.19
ClinPred		0.060	T
GERP RS		4.8
PromoterAI		-0.010	Neutral
Varity_R		0.22
gMVP		0.41
Mutation Taster		=65/35	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: rs149022536; hg19: chr13-49925022; COSMIC: COSV61713679;