rs2069506

Variant names:

• chr12-57749071-C-A
• rs2069506
• NM_005981.5:c.*1781C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57749071-C-A
• chr12-57749071-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005981.5(TSPAN31):​c.*1781C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,346,344 control chromosomes in the GnomAD database, including 81,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6737 hom., cov: 32)
  • Exomes 𝑓: 0.34 (74845 hom.)
• Consequence: TSPAN31 NM_005981.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.205
• Publications: 20 publications found

Genes affected

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

CDK4 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-57749071-C-A is Benign according to our data. Variant chr12-57749071-C-A is described in ClinVar as Benign. ClinVar VariationId is 1182049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPAN31	NM_005981.5	c.*1781C>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1
CDK4	NM_000075.4	c.819+111G>T		intron_variant	Intron 7 of 7	ENST00000257904.11	NP_000066.1
TSPAN31	NM_001330169.2	c.*1781C>A		3_prime_UTR_variant	Exon 6 of 6		NP_001317098.1
TSPAN31	NM_001330168.2	c.*1781C>A		3_prime_UTR_variant	Exon 4 of 4		NP_001317097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPAN31	ENST00000257910.8	c.*1781C>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3
CDK4	ENST00000257904.11	c.819+111G>T		intron_variant	Intron 7 of 7	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40291 AN: 152066 Hom.: 6734 Cov.: 32

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.237

GnomAD4 exome AF: 0.339 AC: 405229 AN: 1194160 Hom.: 74845 Cov.: 17 AF XY: 0.345 AC XY: 208953 AN XY: 606228

African (AFR) AF: 0.0729 AC: 2066 AN: 28342

American (AMR) AF: 0.334 AC: 14740 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7024 AN: 24342

East Asian (EAS) AF: 0.707 AC: 27212 AN: 38474

South Asian (SAS) AF: 0.487 AC: 39147 AN: 80422

European-Finnish (FIN) AF: 0.353 AC: 18775 AN: 53202

Middle Eastern (MID) AF: 0.191 AC: 1005 AN: 5252

European-Non Finnish (NFE) AF: 0.321 AC: 278760 AN: 868486

Other (OTH) AF: 0.320 AC: 16500 AN: 51514

GnomAD4 genome AF: 0.265 AC: 40297 AN: 152184 Hom.: 6737 Cov.: 32 AF XY: 0.273 AC XY: 20302 AN XY: 74406

African (AFR) AF: 0.0818 AC: 3398 AN: 41544

American (AMR) AF: 0.256 AC: 3919 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1004 AN: 3470

East Asian (EAS) AF: 0.655 AC: 3381 AN: 5158

South Asian (SAS) AF: 0.491 AC: 2368 AN: 4818

European-Finnish (FIN) AF: 0.373 AC: 3953 AN: 10592

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21384 AN: 67996

Other (OTH) AF: 0.235 AC: 496 AN: 2108

Alfa AF: 0.279 Hom.: 835

Bravo AF: 0.247

Asia WGS AF: 0.511 AC: 1775 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.6
DANN	Benign	0.60
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2069506; hg19: chr12-58142854;