rs200570912

Variant names:

• chr2-201289745-T-C
• rs200570912
• NM_001127391.3:c.983A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001127391.3(FLACC1):​c.983A>G​(p.Glu328Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,614,148 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: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: FLACC1 NM_001127391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 1 publications found

Genes affected

FLACC1 (HGNC:14439): (flagellum associated containing coiled-coil domains 1) Predicted to be located in cytoplasmic vesicle and sperm flagellum. Predicted to be active in cytoplasm; outer dense fiber; and sperm fibrous sheath. [provided by Alliance of Genome Resources, Apr 2022]

CASP8 (HGNC:1509): (caspase 8) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122241616).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	NM_001127391.3	MANE Select	c.983A>G	p.Glu328Gly	missense	Exon 13 of 15	NP_001120863.1	Q96Q35-2
	FLACC1	NM_139163.4		c.1052A>G	p.Glu351Gly	missense	Exon 13 of 15	NP_631902.2	Q96Q35-1
	FLACC1	NM_001289993.2		c.983A>G	p.Glu328Gly	missense	Exon 13 of 15	NP_001276922.1	Q96Q35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLACC1	ENST00000392257.8	TSL:1 MANE Select	c.983A>G	p.Glu328Gly	missense	Exon 13 of 15	ENSP00000376086.3	Q96Q35-2
	FLACC1	ENST00000286190.9	TSL:1	c.1052A>G	p.Glu351Gly	missense	Exon 12 of 14	ENSP00000286190.5	Q96Q35-1
	FLACC1	ENST00000405148.6	TSL:5	c.1052A>G	p.Glu351Gly	missense	Exon 13 of 15	ENSP00000385098.2	Q96Q35-1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251442 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000187 AC: 273 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 147 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000186 AC: 207 AN: 1111998

Other (OTH) AF: 0.000265 AC: 16 AN: 60394

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000752 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000654

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.0060
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.21
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.026	D
Polyphen		0.87	P
Vest4		0.30
MVP		0.68
MPC		0.28
ClinPred		0.24	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.073
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs200570912; hg19: chr2-202154468;