4-90308376-C-A

Position:

• chr4-90308376-C-A

Variant summary

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

The NM_001145065.2(CCSER1):​c.92C>A​(p.Ser31Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCSER1 NM_001145065.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.28

Genes affected

CCSER1 (HGNC:29349): (coiled-coil serine rich protein 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCSER1	NM_001145065.2	c.92C>A	p.Ser31Tyr	missense_variant	2/11	ENST00000509176.6	NP_001138537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCSER1	ENST00000509176.6	c.92C>A	p.Ser31Tyr	missense_variant	2/11	1	NM_001145065.2	ENSP00000425040.1
CCSER1	ENST00000432775.6	c.92C>A	p.Ser31Tyr	missense_variant	2/8	1		ENSP00000389283.2
CCSER1	ENST00000505073.5	n.92C>A		non_coding_transcript_exon_variant	2/10	1		ENSP00000420964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461430 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726970

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 12, 2024

The c.92C>A (p.S31Y) alteration is located in exon 2 (coding exon 1) of the CCSER1 gene. This alteration results from a C to A substitution at nucleotide position 92, causing the serine (S) at amino acid position 31 to be replaced by a tyrosine (Y). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.97	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.48
MutPred		0.31		Loss of glycosylation at P33 (P = 0.0046);Loss of glycosylation at P33 (P = 0.0046);
MVP		0.61
MPC		0.44
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.46

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: rs1007696750; hg19: chr4-91229527;