11-72841471-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014824.3(FCHSD2):c.2039G>C(p.Arg680Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FCHSD2 NM_014824.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41338426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCHSD2	NM_014824.3	c.2039G>C	p.Arg680Pro	missense_variant	18/20	ENST00000409418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCHSD2	ENST00000409418.9	c.2039G>C	p.Arg680Pro	missense_variant	18/20	2	NM_014824.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458700 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.2039G>C (p.R680P) alteration is located in exon 18 (coding exon 18) of the FCHSD2 gene. This alteration results from a G to C substitution at nucleotide position 2039, causing the arginine (R) at amino acid position 680 to be replaced by a proline (P). 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	0.17
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.66	N;N;N;D;N
REVEL	Benign	0.065
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.43, 0.64	.;.;B;.;P
Vest4		0.56
MutPred		0.26		.;.;Gain of glycosylation at R680 (P = 0.0063);.;.;
MVP		0.45
MPC		0.60
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.18
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-72552516; COSMIC: COSV60813034; COSMIC: COSV60813034;