4-70335463-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033122.4(CABS1):c.424G>A(p.Glu142Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: CABS1 NM_033122.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

CABS1 (HGNC:30710): (calcium binding protein, spermatid associated 1) Predicted to enable calcium ion binding activity. Predicted to be involved in flagellated sperm motility and spermatogenesis. Predicted to be located in acrosomal vesicle and sperm principal piece. Predicted to be active in mitochondrial inner membrane and motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30745292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CABS1	NM_033122.4	c.424G>A	p.Glu142Lys	missense_variant	1/2	ENST00000273936.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CABS1	ENST00000273936.6	c.424G>A	p.Glu142Lys	missense_variant	1/2	1	NM_033122.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 11, 2022

The c.424G>A (p.E142K) alteration is located in exon 1 (coding exon 1) of the CABS1 gene. This alteration results from a G to A substitution at nucleotide position 424, causing the glutamic acid (E) at amino acid position 142 to be replaced by a lysine (K). 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	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.027
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.75	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.072
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		0.48	P
Vest4		0.22
MutPred		0.72		Gain of ubiquitination at E142 (P = 0.0162);
MVP		0.48
MPC		0.17
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.47
gMVP		0.11

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: chr4-71201180;