17-81528536-C-G

Variant names:

• chr17-81528536-C-G
• rs538029653
• NM_012418.4:c.5C>G

Variant summary

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

The NM_012418.4(FSCN2):​c.5C>G​(p.Pro2Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,437,746 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P2L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FSCN2 NM_012418.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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, 0.81

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.5C>G	p.Pro2Arg	missense	Exon 1 of 5	NP_036550.1	O14926-1
	FSCN2	NM_001077182.3		c.5C>G	p.Pro2Arg	missense	Exon 1 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.5C>G	p.Pro2Arg	missense	Exon 1 of 5	ENSP00000388716.2	O14926-1
	FSCN2	ENST00000334850.7	TSL:5	c.5C>G	p.Pro2Arg	missense	Exon 1 of 5	ENSP00000334665.7	O14926-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437746 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 712712

African (AFR) AF: 0.00 AC: 0 AN: 32902

American (AMR) AF: 0.00 AC: 0 AN: 41930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38366

South Asian (SAS) AF: 0.00 AC: 0 AN: 83194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099842

Other (OTH) AF: 0.00 AC: 0 AN: 59426

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.25		Gain of MoRF binding (P = 0.0115)
MVP		0.74
MPC		0.43
ClinPred		0.95	D
GERP RS		4.2
PromoterAI		-0.040	Neutral
Varity_R		0.21
gMVP		0.52
Mutation Taster		=51/49	polymorphism

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: rs538029653; hg19: chr17-79495562;