12-89525131-C-T

Variant names:

• chr12-89525131-C-T
• rs868030435
• NM_172240.3:c.89G>A

Variant summary

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

The NM_172240.3(POC1B):​c.89G>A​(p.Gly30Asp) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POC1B NM_172240.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

Genes affected

POC1B (HGNC:30836): (POC1 centriolar protein B) POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled coil domain and are part of centrosomes. They play an important role in basal body and cilia formation. This gene encodes one of the two POC1 proteins found in humans. Mutation in this gene result in autosomal-recessive cone-rod dystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

POC1B-GALNT4 (HGNC:42957): (POC1B-GALNT4 readthrough) This locus represents naturally occurring transcripts that splice the 5' exons of the POC1B (POC1 centriolar protein homolog B) gene on chromosome 12 to the GALNT4 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 4) gene, which is located within a POC1B intron. Alternative splicing results in two transcript variants, one of which encodes a fusion isoform that shares sequence identity with the products of each individual gene. [provided by RefSeq, Dec 2010]

POC1B-AS1 (HGNC:52949): (POC1B antisense RNA 1)

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=0.23990563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POC1B	NM_172240.3	c.89G>A	p.Gly30Asp	missense_variant	Exon 2 of 12	ENST00000313546.8	NP_758440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POC1B	ENST00000313546.8	c.89G>A	p.Gly30Asp	missense_variant	Exon 2 of 12	1	NM_172240.3	ENSP00000323302.3
POC1B-GALNT4	ENST00000548729.5	c.89G>A	p.Gly30Asp	missense_variant	Exon 2 of 3	2		ENSP00000447852.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POC1B protein function. This variant has not been reported in the literature in individuals affected with POC1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 30 of the POC1B protein (p.Gly30Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.86	D;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.20	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.43	T;D;T
Polyphen		0.16	B;B;.
Vest4		0.52
MutPred		0.34		Gain of catalytic residue at A35 (P = 0.001);Gain of catalytic residue at A35 (P = 0.001);Gain of catalytic residue at A35 (P = 0.001);
MVP		0.69
MPC		0.13
ClinPred		0.92	D
GERP RS		2.6
Varity_R		0.15
gMVP		0.36

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: rs868030435; hg19: chr12-89918908; COSMIC: COSV100544539; COSMIC: COSV100544539;