10-69097207-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002727.4(SRGN):c.203C>G(p.Pro68Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,808 control chromosomes in the GnomAD database, including 156 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (13 hom., cov: 31)
  • Exomes 𝑓: 0.011 (143 hom.)
• Consequence: SRGN NM_002727.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.523

Genes affected

SRGN (HGNC:9361): (serglycin) This gene encodes a protein best known as a hematopoietic cell granule proteoglycan. Proteoglycans stored in the secretory granules of many hematopoietic cells also contain a protease-resistant peptide core, which may be important for neutralizing hydrolytic enzymes. This encoded protein was found to be associated with the macromolecular complex of granzymes and perforin, which may serve as a mediator of granule-mediated apoptosis. Two transcript variants, only one of them protein-coding, have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004487455).
• BP6: Variant 10-69097207-C-G is Benign according to our data. Variant chr10-69097207-C-G is described in ClinVar as [Benign]. Clinvar id is 710351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0097 (1477/152234) while in subpopulation NFE AF= 0.0165 (1120/68016). AF 95% confidence interval is 0.0157. There are 13 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGN	NM_002727.4	c.203C>G	p.Pro68Arg	missense_variant	2/3	ENST00000242465.4
SRGN	NM_001321053.2	c.203C>G	p.Pro68Arg	missense_variant	3/4
SRGN	NM_001321054.1	c.60-6664C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGN	ENST00000242465.4	c.203C>G	p.Pro68Arg	missense_variant	2/3	1	NM_002727.4	P1
SRGN	ENST00000462445.1	n.132-6664C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1478 AN: 152116 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00939 AC: 2361 AN: 251346 Hom.: 19 AF XY: 0.00953 AC XY: 1295 AN XY: 135848

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.0106 AC: 15550 AN: 1461574 Hom.: 143 Cov.: 32 AF XY: 0.0106 AC XY: 7734 AN XY: 727096

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00825

GnomAD4 genome AF: 0.00970 AC: 1477 AN: 152234 Hom.: 13 Cov.: 31 AF XY: 0.00955 AC XY: 711 AN XY: 74436

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0137 Hom.: 19

Bravo AF: 0.00750

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00966 AC: 1173

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.8
Dann	Benign	0.89
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.063
Sift	Benign	0.12	T
Sift4G	Uncertain	0.056	T
Polyphen		0.14	B
Vest4		0.15
MVP		0.32
MPC		0.62
ClinPred		0.021	T
GERP RS		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs67852477; hg19: chr10-70856963; COSMIC: COSV54344349; COSMIC: COSV54344349;