chr17-81535192-G-A

Position:

• chr17-81535192-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012418.4(FSCN2):​c.967G>A​(p.Ala323Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,530,642 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (66 hom., cov: 31)
  • Exomes 𝑓: 0.033 (842 hom.)
• Consequence: FSCN2 NM_012418.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.815

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032982528).
• BP6: Variant 17-81535192-G-A is Benign according to our data. Variant chr17-81535192-G-A is described in ClinVar as [Benign]. Clinvar id is 402883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81535192-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0256 (3891/151798) while in subpopulation NFE AF= 0.0375 (2545/67880). AF 95% confidence interval is 0.0363. There are 66 homozygotes in gnomad4. There are 1883 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3891 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FSCN2	NM_012418.4	c.967G>A	p.Ala323Thr	missense_variant	2/5	ENST00000417245.7	NP_036550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FSCN2	ENST00000417245.7	c.967G>A	p.Ala323Thr	missense_variant	2/5	1	NM_012418.4	ENSP00000388716.2
FSCN2	ENST00000334850.7	c.967G>A	p.Ala323Thr	missense_variant	2/5	5		ENSP00000334665.7

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3892 AN: 151680 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.00669

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0613

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00623

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0360

GnomAD3 exomes AF: 0.0267 AC: 3616 AN: 135440 Hom.: 74 AF XY: 0.0264 AC XY: 1926 AN XY: 72836

Gnomad AFR exome AF: 0.00559

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0569

Gnomad EAS exome AF: 0.0000998

Gnomad SAS exome AF: 0.00688

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0332 AC: 45783 AN: 1378844 Hom.: 842 Cov.: 31 AF XY: 0.0328 AC XY: 22346 AN XY: 680324

Gnomad4 AFR exome AF: 0.00669

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0580

Gnomad4 EAS exome AF: 0.0000566

Gnomad4 SAS exome AF: 0.00689

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0324

GnomAD4 genome AF: 0.0256 AC: 3891 AN: 151798 Hom.: 66 Cov.: 31 AF XY: 0.0254 AC XY: 1883 AN XY: 74186

Gnomad4 AFR AF: 0.00667

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0613

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00624

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0356

Alfa AF: 0.0374 Hom.: 88

Bravo AF: 0.0248

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.00506 AC: 7

ESP6500EA AF: 0.0361 AC: 115

ExAC AF: 0.0151 AC: 411

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.093
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.65	P;.
Vest4		0.34
MPC		0.20
ClinPred		0.0091	T
GERP RS		3.9
Varity_R		0.18
gMVP		0.39

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: rs186367879; hg19: chr17-79502218;