16-2896526-C-G

Position:

• chr16-2896526-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138439.3(FLYWCH2):​c.77C>G​(p.Thr26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLYWCH2 NM_138439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.271

Genes affected

FLYWCH2 (HGNC:25178): (FLYWCH family member 2) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11792219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLYWCH2	NM_138439.3	c.77C>G	p.Thr26Arg	missense_variant	3/4	ENST00000396958.8	NP_612448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLYWCH2	ENST00000396958.8	c.77C>G	p.Thr26Arg	missense_variant	3/4	1	NM_138439.3	ENSP00000380159.3
FLYWCH2	ENST00000572006.1	c.77C>G	p.Thr26Arg	missense_variant	3/3	2		ENSP00000459223.1
FLYWCH2	ENST00000293981.10	c.77C>G	p.Thr26Arg	missense_variant	3/4	3		ENSP00000293981.6
FLYWCH2	ENST00000573965.1	c.77C>G	p.Thr26Arg	missense_variant	2/2	2		ENSP00000461275.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Oct 03, 2023

The c.77C>G (p.T26R) alteration is located in exon 3 (coding exon 1) of the FLYWCH2 gene. This alteration results from a C to G substitution at nucleotide position 77, causing the threonine (T) at amino acid position 26 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.5	D;D;.;.
REVEL	Benign	0.033
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.98	D;D;.;.
Vest4		0.48
MutPred		0.23		Loss of phosphorylation at T26 (P = 0.0182);Loss of phosphorylation at T26 (P = 0.0182);Loss of phosphorylation at T26 (P = 0.0182);Loss of phosphorylation at T26 (P = 0.0182);
MVP		0.10
MPC		0.55
ClinPred		0.91	D
GERP RS		-0.18
Varity_R		0.46
gMVP		0.27

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: rs1407163112; hg19: chr16-2946527;