NM_172240.3:c.317G>C

Variant names:

• chr12-89492071-C-G
• rs76216585
• NM_172240.3:c.317G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_172240.3(POC1B):​c.317G>C​(p.Arg106Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,597,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: POC1B NM_172240.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 20

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POC1B-DUSP6 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 12-89492071-C-G is Pathogenic according to our data. Variant chr12-89492071-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 155769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172240.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POC1B	NM_172240.3	MANE Select	c.317G>C	p.Arg106Pro	missense	Exon 4 of 12	NP_758440.1	Q8TC44-1
	POC1B	NM_001199777.2		c.191G>C	p.Arg64Pro	missense	Exon 3 of 11	NP_001186706.1	Q8TC44-2
	POC1B	NM_001425771.1		c.317G>C	p.Arg106Pro	missense	Exon 4 of 12	NP_001412700.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POC1B	ENST00000313546.8	TSL:1 MANE Select	c.317G>C	p.Arg106Pro	missense	Exon 4 of 12	ENSP00000323302.3	Q8TC44-1
	POC1B	ENST00000393179.8	TSL:1	c.-74G>C		5_prime_UTR	Exon 2 of 10	ENSP00000376877.4	Q8IU52
	POC1B	ENST00000928754.1		c.317G>C	p.Arg106Pro	missense	Exon 4 of 12	ENSP00000598813.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1445450 Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 8 AN XY: 718744

African (AFR) AF: 0.00 AC: 0 AN: 32508

American (AMR) AF: 0.00 AC: 0 AN: 40058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 82470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1107060

Other (OTH) AF: 0.00 AC: 0 AN: 59666

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cone-rod dystrophy 20 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.54		Gain of catalytic residue at F110 (P = 0.0017)
MVP		0.88
MPC		0.45
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.80
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs76216585; hg19: chr12-89885848;