chr19-4262065-C-T

Variant names:

• chr19-4262065-C-T
• rs151025034
• NM_018074.6:c.659C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018074.6(YJU2):​c.659C>T​(p.Ser220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: YJU2 NM_018074.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119

Genes affected

YJU2 (HGNC:25518): (YJU2 splicing factor homolog) Predicted to enable metal ion binding activity. Predicted to be involved in RNA splicing and negative regulation of DNA damage response, signal transduction by p53 class mediator. Part of U2-type catalytic step 1 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity YJU2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07492387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YJU2	NM_018074.6	c.659C>T	p.Ser220Leu	missense_variant	Exon 6 of 8	ENST00000262962.12	NP_060544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YJU2	ENST00000262962.12	c.659C>T	p.Ser220Leu	missense_variant	Exon 6 of 8	1	NM_018074.6	ENSP00000262962.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460242 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726476

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.659C>T (p.S220L) alteration is located in exon 6 (coding exon 6) of the CCDC94 gene. This alteration results from a C to T substitution at nucleotide position 659, causing the serine (S) at amino acid position 220 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	0.064
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.1
DANN	Benign	0.83
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.0060
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.14	B
Vest4		0.11
MVP		0.15
MPC		0.077
ClinPred		0.040	T
GERP RS		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.11

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: rs151025034; hg19: chr19-4262062;