12-89425162-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_172240.3(POC1B):c.1331A>G(p.Gln444Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POC1B NM_172240.3 missense, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POC1B	NM_172240.3	c.1331A>G	p.Gln444Arg	missense_variant, splice_region_variant	11/12	ENST00000313546.8
POC1B	NM_001199777.2	c.1205A>G	p.Gln402Arg	missense_variant, splice_region_variant	10/11
POC1B	NR_037659.2	n.1334A>G		splice_region_variant, non_coding_transcript_exon_variant	11/12
POC1B	NR_037660.2	n.1370A>G		splice_region_variant, non_coding_transcript_exon_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POC1B	ENST00000313546.8	c.1331A>G	p.Gln444Arg	missense_variant, splice_region_variant	11/12	1	NM_172240.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727104

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0068	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Benign	0.17
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	D;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.22
Sift	Benign	0.041	D;D;D
Sift4G	Benign	0.085	T;T;T
Polyphen		0.92	.;P;.
Vest4		0.31
MutPred		0.46		.;Gain of catalytic residue at Q444 (P = 0.009);.;
MVP		0.69
MPC		0.077
ClinPred		0.82	D
GERP RS		4.6
Varity_R		0.12
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555215866; hg19: chr12-89818939;