chr4-70335580-C-G

Position:

• chr4-70335580-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000273936.6(CABS1):​c.541C>G​(p.Arg181Gly) 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. 15/21 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 ENST00000273936.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038123637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABS1	NM_033122.4	c.541C>G	p.Arg181Gly	missense_variant	1/2	ENST00000273936.6	NP_149113.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CABS1	ENST00000273936.6	c.541C>G	p.Arg181Gly	missense_variant	1/2	1	NM_033122.4	ENSP00000273936	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135036

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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

Mar 08, 2024

The c.541C>G (p.R181G) alteration is located in exon 1 (coding exon 1) of the CABS1 gene. This alteration results from a C to G substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a glycine (G). 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	0.083
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.3
DANN	Benign	0.13
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00064	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.029
Sift	Benign	0.64	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.12
MPC		0.052
ClinPred		0.049	T
GERP RS		1.1
Varity_R		0.047
gMVP		0.0079

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs761637105; hg19: chr4-71201297; COSMIC: COSV105087508;