Genetic Variant NM_172240.3:c.317G>A (chr12-89492071-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_ModerateBP6_Moderate

The NM_172240.3(POC1B):c.317G>A(p.Arg106Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,597,748 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

POC1B
NM_172240.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a repeat WD 3 (size 38) in uniprot entity POC1B_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_172240.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-89492071-C-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.19926763).

BP6

Variant 12-89492071-C-T is Benign according to our data. Variant chr12-89492071-C-T is described in ClinVar as [Benign]. Clinvar id is 851405.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POC1B	NM_172240.3 link	c.317G>A	p.Arg106Gln	missense_variant	Exon 4 of 12	ENST00000313546.8	NP_758440.1	Q8TC44-1A0MNP0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POC1B	ENST00000313546.8 link	c.317G>A	p.Arg106Gln	missense_variant	Exon 4 of 12	1	NM_172240.3	ENSP00000323302.3		Q8TC44-1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000269

AC:

AN:

234288

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

126898

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.000271

Gnomad ASJ exome

AF:

0.000220

Gnomad EAS exome

AF:

0.0000578

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.000353

GnomAD4 exome

AF:

0.000208

AC:

301

AN:

1445448

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

146

AN XY:

718742

show subpopulations

Gnomad4 AFR exome

AF:

0.0000615

Gnomad4 AMR exome

AF:

0.000275

Gnomad4 ASJ exome

AF:

0.000118

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000322

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000365

Hom.:

Bravo

AF:

0.000397

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000346

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinal dystrophy

Uncertain:1

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.8

L;.

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.90

MVP

0.84

MPC

0.40

ClinPred

0.41

GERP RS

5.8

Varity_R

0.71

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over