Variant 11-72867866-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014824.3(FCHSD2):c.1307C>T(p.Ser436Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000633 in 1,610,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

FCHSD2
NM_014824.3 missense, splice_region

Scores

Splicing: ADA: 0.3262

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76

Variant links:

Genes affected

FCHSD2 (HGNC:29114): (FCH and double SH3 domains 2) Enables phosphatidylinositol-3,4,5-trisphosphate binding activity and phosphatidylinositol-3,4-bisphosphate binding activity. Involved in clathrin-dependent endocytosis and positive regulation of Arp2/3 complex-mediated actin nucleation. Located in plasma membrane. Colocalizes with clathrin-coated pit. [provided by Alliance of Genome Resources, Apr 2022]

FCHSD2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028624237).

BS2

High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCHSD2	NM_014824.3 linkuse as main transcript	c.1307C>T	p.Ser436Leu	missense_variant, splice_region_variant	13/20	ENST00000409418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHSD2	ENST00000409418.9 linkuse as main transcript	c.1307C>T	p.Ser436Leu	missense_variant, splice_region_variant	13/20	2	NM_014824.3	P1	O94868-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000851

AC:

AN:

246912

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

133254

show subpopulations

Gnomad AFR exome

AF:

0.000688

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000135

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000487

AC:

AN:

1458632

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

725274

show subpopulations

Gnomad4 AFR exome

AF:

0.000479

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000258

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000204

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000504

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The c.1307C>T (p.S436L) alteration is located in exon 13 (coding exon 13) of the FCHSD2 gene. This alteration results from a C to T substitution at nucleotide position 1307, causing the serine (S) at amino acid position 436 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.46

Cadd

Benign

Dann

Benign

0.95

Eigen

Benign

-0.14

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.029

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.74

D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Benign

0.067

Sift

Benign

0.22

T;T;T;T;T

Sift4G

Benign

0.36

T;T;T;T;T

Polyphen

0.0

.;.;B;B;B

Vest4

0.098

MVP

0.42

MPC

0.21

ClinPred

0.037

GERP RS

4.7

Varity_R

0.047

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.33

dbscSNV1_RF

Benign

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over