9-17135105-C-T

Position:

• chr9-17135105-C-T

Variant summary

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

The NM_017738.4(CNTLN):​c.40C>T​(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNTLN NM_017738.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0840

Genes affected

CNTLN (HGNC:23432): (centlein) Enables protein domain specific binding activity; protein kinase binding activity; and protein-macromolecule adaptor activity. Involved in centriole-centriole cohesion and protein localization to organelle. Located in cytosol; microtubule organizing center; and nucleoplasm. [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=0.049919248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTLN	NM_017738.4	c.40C>T	p.Pro14Ser	missense_variant	1/26	ENST00000380647.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTLN	ENST00000380647.8	c.40C>T	p.Pro14Ser	missense_variant	1/26	1	NM_017738.4	P1
CNTLN	ENST00000380641.4	c.40C>T	p.Pro14Ser	missense_variant	1/7	2
CNTLN	ENST00000484374.1	n.124C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453564 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 722570

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000166 AC: 2

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 17, 2023

The c.40C>T (p.P14S) alteration is located in exon 1 (coding exon 1) of the CNTLN gene. This alteration results from a C to T substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a serine (S). 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
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0020	B;B
Vest4		0.14
MutPred		0.18		Gain of phosphorylation at P14 (P = 0.0045);Gain of phosphorylation at P14 (P = 0.0045);
MVP		0.014
ClinPred		0.067	T
GERP RS		-0.14
gMVP		0.086

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: rs757057300; hg19: chr9-17135103;