chr12-57747819-C-T

Variant names:

• chr12-57747819-C-T
• rs184712
• NM_000075.4:c.*706G>A

Variant summary

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

The NM_000075.4(CDK4):​c.*706G>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 0.212 in 168,038 control chromosomes in the GnomAD database, including 4,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3958 hom., cov: 31)
  • Exomes 𝑓: 0.15 (243 hom.)
• Consequence: CDK4 NM_000075.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.323
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-57747819-C-T is Benign according to our data. Variant chr12-57747819-C-T is described in ClinVar as Benign. ClinVar VariationId is 309965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

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.*706G>A		3_prime_UTR	Exon 8 of 8	NP_000066.1	P11802-1
	TSPAN31	NM_005981.5	MANE Select	c.*529C>T		3_prime_UTR	Exon 6 of 6	NP_005972.1	Q12999
	TSPAN31	NM_001330169.2		c.*529C>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.*706G>A		3_prime_UTR	Exon 8 of 8	ENSP00000257904.5	P11802-1
	TSPAN31	ENST00000257910.8	TSL:1 MANE Select	c.*529C>T		3_prime_UTR	Exon 6 of 6	ENSP00000257910.3	Q12999
	TSPAN31	ENST00000547992.5	TSL:1	c.*529C>T		3_prime_UTR	Exon 4 of 4	ENSP00000448209.1	F8VS78

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33185 AN: 151684 Hom.: 3953 Cov.: 31

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.149 AC: 2413 AN: 16238 Hom.: 243 Cov.: 0 AF XY: 0.147 AC XY: 1148 AN XY: 7802

African (AFR) AF: 0.234 AC: 90 AN: 384

American (AMR) AF: 0.267 AC: 221 AN: 828

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 76 AN: 870

East Asian (EAS) AF: 0.0818 AC: 234 AN: 2862

South Asian (SAS) AF: 0.154 AC: 65 AN: 422

European-Finnish (FIN) AF: 0.179 AC: 10 AN: 56

Middle Eastern (MID) AF: 0.180 AC: 18 AN: 100

European-Non Finnish (NFE) AF: 0.160 AC: 1531 AN: 9586

Other (OTH) AF: 0.149 AC: 168 AN: 1130

GnomAD4 genome AF: 0.219 AC: 33207 AN: 151800 Hom.: 3958 Cov.: 31 AF XY: 0.215 AC XY: 15979 AN XY: 74172

African (AFR) AF: 0.284 AC: 11767 AN: 41370

American (AMR) AF: 0.287 AC: 4380 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 390 AN: 3464

East Asian (EAS) AF: 0.101 AC: 523 AN: 5170

South Asian (SAS) AF: 0.147 AC: 709 AN: 4820

European-Finnish (FIN) AF: 0.187 AC: 1966 AN: 10496

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12739 AN: 67922

Other (OTH) AF: 0.198 AC: 418 AN: 2106

Alfa AF: 0.207 Hom.: 431

Bravo AF: 0.235

Asia WGS AF: 0.112 AC: 390 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	-0.93
CADD	Benign	1.0
DANN	Benign	0.64
PhyloP100		-0.32
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: rs184712; hg19: chr12-58141602;