17-81528580-G-A

Position:

• chr17-81528580-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012418.4(FSCN2):​c.49G>A​(p.Val17Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,608,570 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: FSCN2 NM_012418.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014135033).
• BP6: Variant 17-81528580-G-A is Benign according to our data. Variant chr17-81528580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 100561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81528580-G-A is described in Lovd as [Benign]. Variant chr17-81528580-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSCN2	NM_012418.4	c.49G>A	p.Val17Ile	missense_variant	1/5	ENST00000417245.7	NP_036550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSCN2	ENST00000417245.7	c.49G>A	p.Val17Ile	missense_variant	1/5	1	NM_012418.4	ENSP00000388716	P1
FSCN2	ENST00000334850.7	c.49G>A	p.Val17Ile	missense_variant	1/5	5		ENSP00000334665

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152250 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00229 AC: 546 AN: 238348 Hom.: 2 AF XY: 0.00235 AC XY: 306 AN XY: 130088

Gnomad AFR exome AF: 0.000481

Gnomad AMR exome AF: 0.000887

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.000171

Gnomad SAS exome AF: 0.000743

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00345 AC: 5021 AN: 1456202 Hom.: 12 Cov.: 32 AF XY: 0.00333 AC XY: 2413 AN XY: 723966

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.000749

Gnomad4 FIN exome AF: 0.00492

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00254

GnomAD4 genome AF: 0.00242 AC: 369 AN: 152368 Hom.: 1 Cov.: 34 AF XY: 0.00231 AC XY: 172 AN XY: 74520

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00332 Hom.: 3

Bravo AF: 0.00207

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000958 AC: 4

ESP6500EA AF: 0.00262 AC: 22

ExAC AF: 0.00215 AC: 260

ClinVar

Significance: Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 30 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 28, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Dec 09, 2015	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.028
DANN	Benign	0.86
DEOGEN2	Benign	0.074	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.1	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.48	N;N
REVEL	Benign	0.088
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.064
MVP		0.061
MPC		0.060
ClinPred		0.0059	T
GERP RS		-5.3
Varity_R		0.019
gMVP		0.12

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

Other links and lift over

dbSNP: rs137853900; hg19: chr17-79495606;