4-70335931-T-G

Position:

• chr4-70335931-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033122.4(CABS1):​c.892T>G​(p.Trp298Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0974 in 1,613,402 control chromosomes in the GnomAD database, including 9,355 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.085 (808 hom., cov: 32)
  • Exomes 𝑓: 0.099 (8547 hom.)
• Consequence: CABS1 NM_033122.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019220412).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CABS1	NM_033122.4	c.892T>G	p.Trp298Gly	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.892T>G	p.Trp298Gly	missense_variant	1/2	1	NM_033122.4	ENSP00000273936	P1

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12944 AN: 151854 Hom.: 807 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.0944

GnomAD3 exomes AF: 0.114 AC: 28706 AN: 250912 Hom.: 2199 AF XY: 0.121 AC XY: 16414 AN XY: 135586

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.0934

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.0987 AC: 144260 AN: 1461428 Hom.: 8547 Cov.: 37 AF XY: 0.102 AC XY: 74040 AN XY: 727024

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.0585

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.0854

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.0852 AC: 12948 AN: 151974 Hom.: 808 Cov.: 32 AF XY: 0.0921 AC XY: 6843 AN XY: 74280

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0841

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.0869

Gnomad4 OTH AF: 0.0958

Alfa AF: 0.0938 Hom.: 1965

Bravo AF: 0.0738

TwinsUK AF: 0.0901 AC: 334

ALSPAC AF: 0.0872 AC: 336

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0885 AC: 761

ExAC AF: 0.113 AC: 13770

Asia WGS AF: 0.184 AC: 640 AN: 3476

EpiCase AF: 0.0975

EpiControl AF: 0.0994

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.13	P
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-12	D
REVEL	Benign	0.22
Sift	Benign	0.048	D
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.31
MPC		0.36
ClinPred		0.054	T
GERP RS		4.8
Varity_R		0.29
gMVP		0.0091

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

LitVar

Other links and lift over

dbSNP: rs2291182; hg19: chr4-71201648; COSMIC: COSV56732892;