11-72841559-C-T

Variant summary

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

The NM_014824.3(FCHSD2):​c.1951G>A​(p.Ala651Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,609,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FCHSD2
NM_014824.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0470
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]
ATG16L2 (HGNC:25464): (autophagy related 16 like 2) Predicted to be involved in autophagosome assembly and negative stranded viral RNA replication. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.022967964).
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FCHSD2NM_014824.3 linkc.1951G>A p.Ala651Thr missense_variant Exon 18 of 20 ENST00000409418.9 NP_055639.2 O94868-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FCHSD2ENST00000409418.9 linkc.1951G>A p.Ala651Thr missense_variant Exon 18 of 20 2 NM_014824.3 ENSP00000386722.4 O94868-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000413
AC:
10
AN:
242328
Hom.:
0
AF XY:
0.0000611
AC XY:
8
AN XY:
130974
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000120
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000168
Gnomad SAS exome
AF:
0.000102
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1457330
Hom.:
0
Cov.:
33
AF XY:
0.0000179
AC XY:
13
AN XY:
724606
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000182
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000352
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151818
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74140
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1951G>A (p.A651T) alteration is located in exon 18 (coding exon 18) of the FCHSD2 gene. This alteration results from a G to A substitution at nucleotide position 1951, causing the alanine (A) at amino acid position 651 to be replaced by a threonine (T). 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
0.063
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
8.6
DANN
Benign
0.76
DEOGEN2
Benign
0.018
.;.;T;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.82
T;T;T;T;T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.023
T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-1.1
.;.;N;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.28
N;N;N;N;N
REVEL
Benign
0.064
Sift
Benign
0.81
T;T;T;T;T
Sift4G
Benign
0.33
T;T;T;T;T
Polyphen
0.0
.;.;B;.;B
Vest4
0.12
MutPred
0.18
.;.;Gain of glycosylation at A651 (P = 0.0131);.;.;
MVP
0.22
MPC
0.23
ClinPred
0.028
T
GERP RS
-3.6
Varity_R
0.015
gMVP
0.36

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

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

Other links and lift over

dbSNP: rs757189973; hg19: chr11-72552604; API