4-70335239-A-C

Variant summary

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

The NM_033122.4(CABS1):c.200A>C(p.Lys67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CABS1 NM_033122.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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=0.3378088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CABS1	NM_033122.4	c.200A>C	p.Lys67Thr	missense_variant	1/2	ENST00000273936.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CABS1	ENST00000273936.6	c.200A>C	p.Lys67Thr	missense_variant	1/2	1	NM_033122.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461428 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 26, 2023

The c.200A>C (p.K67T) alteration is located in exon 1 (coding exon 1) of the CABS1 gene. This alteration results from a A to C substitution at nucleotide position 200, causing the lysine (K) at amino acid position 67 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.066
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.33		Loss of ubiquitination at K67 (P = 0.0118);
MVP		0.57
MPC		0.31
ClinPred		0.98	D
GERP RS		2.4
Varity_R		0.53
gMVP		0.040

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: rs1731692433; hg19: chr4-71200956;