12-53269738-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_012291.5(ESPL1):c.796C>T(p.Arg266Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,010 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: ESPL1 NM_012291.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96

Genes affected

ESPL1 (HGNC:16856): (extra spindle pole bodies like 1, separase) Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 (MIM 604358) or STAG2 (MIM 300826) in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21; MIM 606462) by ESPL1, or separase, which initiates the final separation of sister chromatids (Sun et al., 2009 [PubMed 19345191]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ESPL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.024828464).
• BP6: Variant 12-53269738-C-T is Benign according to our data. Variant chr12-53269738-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2564444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPL1	NM_012291.5	c.796C>T	p.Arg266Cys	missense_variant	3/31	ENST00000257934.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPL1	ENST00000257934.9	c.796C>T	p.Arg266Cys	missense_variant	3/31	5	NM_012291.5	P1
ESPL1	ENST00000552671.5	c.*727C>T		3_prime_UTR_variant, NMD_transcript_variant	3/31	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251394 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461862 Hom.: 0 Cov.: 34 AF XY: 0.0000344 AC XY: 25 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.0000414

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	10
Dann	Benign	0.65
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.0030
Sift	Benign	0.13	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0010	B;B
Vest4		0.11
MVP		0.068
MPC		0.89
ClinPred		0.029	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.13

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: rs372670255; hg19: chr12-53663522; COSMIC: COSV57762941; COSMIC: COSV57762941;