12-57748315-C-T

Variant names:

• chr12-57748315-C-T
• rs2069511
• NM_000075.4:c.*210G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000075.4(CDK4):​c.*210G>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 0.0028 in 588,326 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (1 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.168
• Publications: 3 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-57748315-C-T is Benign according to our data. Variant chr12-57748315-C-T is described in ClinVar as Benign. ClinVar VariationId is 309977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 407 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000075.4. 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
	CDK4	NM_000075.4	MANE Select	c.*210G>A		3_prime_UTR	Exon 8 of 8	NP_000066.1	P11802-1
	TSPAN31	NM_005981.5	MANE Select	c.*1025C>T		3_prime_UTR	Exon 6 of 6	NP_005972.1	Q12999
	TSPAN31	NM_001330169.2		c.*1025C>T		3_prime_UTR	Exon 6 of 6	NP_001317098.1	B4DFJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK4	ENST00000257904.11	TSL:1 MANE Select	c.*210G>A		3_prime_UTR	Exon 8 of 8	ENSP00000257904.5	P11802-1
	TSPAN31	ENST00000257910.8	TSL:1 MANE Select	c.*1025C>T		3_prime_UTR	Exon 6 of 6	ENSP00000257910.3	Q12999
	TSPAN31	ENST00000547992.5	TSL:1	c.*1025C>T		3_prime_UTR	Exon 4 of 4	ENSP00000448209.1	F8VS78

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 407 AN: 151188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000706

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00599

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00193

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00671

GnomAD4 exome AF: 0.00284 AC: 1241 AN: 437028 Hom.: 1 Cov.: 0 AF XY: 0.00262 AC XY: 618 AN XY: 235854

African (AFR) AF: 0.000941 AC: 12 AN: 12750

American (AMR) AF: 0.00555 AC: 128 AN: 23046

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 41 AN: 13362

East Asian (EAS) AF: 0.00 AC: 0 AN: 29164

South Asian (SAS) AF: 0.000253 AC: 13 AN: 51338

European-Finnish (FIN) AF: 0.000858 AC: 22 AN: 25630

Middle Eastern (MID) AF: 0.00567 AC: 10 AN: 1764

European-Non Finnish (NFE) AF: 0.00366 AC: 935 AN: 255462

Other (OTH) AF: 0.00326 AC: 80 AN: 24512

GnomAD4 genome AF: 0.00269 AC: 407 AN: 151298 Hom.: 0 Cov.: 32 AF XY: 0.00261 AC XY: 193 AN XY: 73852

African (AFR) AF: 0.000704 AC: 29 AN: 41170

American (AMR) AF: 0.00599 AC: 91 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00193 AC: 20 AN: 10366

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00357 AC: 242 AN: 67868

Other (OTH) AF: 0.00665 AC: 14 AN: 2104

Alfa AF: 0.00314 Hom.: 1

Bravo AF: 0.00277

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.2
DANN	Benign	0.55
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2069511; hg19: chr12-58142098; COSMIC: COSV107242816;