17-81535192-G-C

Variant names:

• chr17-81535192-G-C
• rs186367879
• NM_012418.4:c.967G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012418.4(FSCN2):​c.967G>C​(p.Ala323Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A323T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FSCN2 NM_012418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.815
• Publications: 9 publications found

Genes affected

FSCN2 (HGNC:3960): (fascin actin-bundling protein 2, retinal) This gene encodes a member of the fascin protein family. Fascins crosslink actin into filamentous bundles within dynamic cell extensions. This family member is proposed to play a role in photoreceptor disk morphogenesis. A mutation in this gene results in one form of autosomal dominant retinitis pigmentosa and macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

FSCN2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 30

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012418.4. 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
	FSCN2	NM_012418.4	MANE Select	c.967G>C	p.Ala323Pro	missense	Exon 2 of 5	NP_036550.1	O14926-1
	FSCN2	NM_001077182.3		c.967G>C	p.Ala323Pro	missense	Exon 2 of 5	NP_001070650.1	O14926-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FSCN2	ENST00000417245.7	TSL:1 MANE Select	c.967G>C	p.Ala323Pro	missense	Exon 2 of 5	ENSP00000388716.2	O14926-1
	FSCN2	ENST00000334850.7	TSL:5	c.967G>C	p.Ala323Pro	missense	Exon 2 of 5	ENSP00000334665.7	O14926-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 269

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.81
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.52
MutPred		0.78		Loss of sheet (P = 0.0357)
MVP		0.65
MPC		0.46
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.70
gMVP		0.82

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: rs186367879; hg19: chr17-79502218;