4-90308527-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145065.2(CCSER1):c.243G>C(p.Glu81Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCSER1 NM_001145065.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.293

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015971512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCSER1	NM_001145065.2	c.243G>C	p.Glu81Asp	missense_variant	2/11	ENST00000509176.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCSER1	ENST00000509176.6	c.243G>C	p.Glu81Asp	missense_variant	2/11	1	NM_001145065.2	P1
CCSER1	ENST00000432775.6	c.243G>C	p.Glu81Asp	missense_variant	2/8	1
CCSER1	ENST00000505073.5	c.243G>C	p.Glu81Asp	missense_variant, NMD_transcript_variant	2/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248584 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461658 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

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

Feb 07, 2023

The c.243G>C (p.E81D) alteration is located in exon 2 (coding exon 1) of the CCSER1 gene. This alteration results from a G to C substitution at nucleotide position 243, causing the glutamic acid (E) at amino acid position 81 to be replaced by an aspartic acid (D). 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	0.066
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.27
Dann	Benign	0.89
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.023
Sift	Benign	0.62	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;B
Vest4		0.061
MutPred		0.14		Gain of glycosylation at S76 (P = 0.0179);Gain of glycosylation at S76 (P = 0.0179);
MVP		0.040
MPC		0.059
ClinPred		0.052	T
GERP RS		-7.7
Varity_R		0.049
gMVP		0.043

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: rs768562667; hg19: chr4-91229678;