17-20096686-T-G

Variant names:

• chr17-20096686-T-G
• rs146091398
• NM_001243439.2:c.35T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001243439.2(SPECC1):​c.35T>G​(p.Ile12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,614,050 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (26 hom.)
• Consequence: SPECC1 NM_001243439.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.833
• Publications: 5 publications found

Genes affected

SPECC1 (HGNC:30615): (sperm antigen with calponin homology and coiled-coil domains 1) The protein encoded by this gene belongs to the cytospin-A family. It is localized in the nucleus, and highly expressed in testis and some cancer cell lines. A chromosomal translocation involving this gene and platelet-derived growth factor receptor, beta gene (PDGFRB) may be a cause of juvenile myelomonocytic leukemia. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005391568).
• BP6: Variant 17-20096686-T-G is Benign according to our data. Variant chr17-20096686-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3770468.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243439.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1	NM_001243439.2	MANE Select	c.35T>G	p.Ile12Ser	missense	Exon 2 of 15	NP_001230368.1	Q5M775-1
	SPECC1	NM_001033553.3		c.35T>G	p.Ile12Ser	missense	Exon 2 of 15	NP_001028725.1	Q5M775-1
	SPECC1	NM_001386083.2		c.35T>G	p.Ile12Ser	missense	Exon 4 of 17	NP_001373012.2	Q5M775-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1	ENST00000395527.9	TSL:2 MANE Select	c.35T>G	p.Ile12Ser	missense	Exon 2 of 15	ENSP00000378898.4	Q5M775-1
	SPECC1	ENST00000261503.9	TSL:1	c.35T>G	p.Ile12Ser	missense	Exon 2 of 15	ENSP00000261503.5	Q5M775-1
	SPECC1	ENST00000395529.7	TSL:1	c.35T>G	p.Ile12Ser	missense	Exon 2 of 8	ENSP00000378900.3	Q5M775-2

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 479 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00336 AC: 843 AN: 251182 AF XY: 0.00351

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00516 AC: 7549 AN: 1461722 Hom.: 26 Cov.: 29 AF XY: 0.00513 AC XY: 3730 AN XY: 727118

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86232

European-Finnish (FIN) AF: 0.00322 AC: 172 AN: 53412

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00603 AC: 6709 AN: 1111906

Other (OTH) AF: 0.00503 AC: 304 AN: 60386

GnomAD4 genome AF: 0.00314 AC: 479 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74510

African (AFR) AF: 0.00125 AC: 52 AN: 41570

American (AMR) AF: 0.00118 AC: 18 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00523 AC: 356 AN: 68016

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00303

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00356 AC: 432

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.69
DANN	Benign	0.79
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.83
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.025
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.24
MVP		0.088
MPC		0.12
ClinPred		0.0012	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.12
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs146091398; hg19: chr17-19999999;