20-56004146-G-A

Variant names:

• chr20-56004146-G-A
• NM_080617.6:c.26C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080617.6(CBLN4):​c.26C>T​(p.Ser9Phe) 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. 12/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBLN4 NM_080617.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

CBLN4 (HGNC:16231): (cerebellin 4 precursor) This gene encodes a member of a family of small secreted proteins containing C1Q domains. Members of this family are involved in regulation of neurexin signalling during synapse development. The mouse homolog of the protein encoded by this gene competes with netrin to bind to the deleted in colorectal cancer receptor. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12350777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLN4	NM_080617.6	c.26C>T	p.Ser9Phe	missense_variant	Exon 1 of 3	ENST00000064571.3	NP_542184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLN4	ENST00000064571.3	c.26C>T	p.Ser9Phe	missense_variant	Exon 1 of 3	1	NM_080617.6	ENSP00000064571.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405622 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695672

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26C>T (p.S9F) alteration is located in exon 1 (coding exon 1) of the CBLN4 gene. This alteration results from a C to T substitution at nucleotide position 26, causing the serine (S) at amino acid position 9 to be replaced by a phenylalanine (F). 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	0.076
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.40	T
Polyphen		0.010	B
Vest4		0.14
MutPred		0.33		Gain of sheet (P = 0.0125);
MVP		0.93
MPC		2.1
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.14
gMVP		0.51

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: chr20-54579202;