12-4273870-C-T

Variant names:

• chr12-4273870-C-T
• rs1049606
• ENST00000674624.1:n.-171C>T

Variant summary

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

The ENST00000674624.1(ENSG00000285901):​n.-171C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 661,906 control chromosomes in the GnomAD database, including 112,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25784 hom., cov: 31)
  • Exomes 𝑓: 0.58 (86416 hom.)
• Consequence: ENSG00000285901 ENST00000674624.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.88
• Publications: 19 publications found

Genes affected

ENSG00000285901 (HGNC:):

CCND2 (HGNC:1583): (cyclin D2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK4 or CDK6 and functions as a regulatory subunit of the complex, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors. Mutations in this gene are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (MPPH3). [provided by RefSeq, Sep 2014]

CCND2-AS1 (HGNC:49398): (CCND2 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-4273870-C-T is Benign according to our data. Variant chr12-4273870-C-T is described in ClinVar as Benign. ClinVar VariationId is 678294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND2	NM_001759.4	c.-171C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000261254.8	NP_001750.1
CCND2-AS1	NR_125790.1	n.126+2189G>A		intron_variant	Intron 1 of 1
CCND2-AS1	NR_149145.1	n.182+1426G>A		intron_variant	Intron 1 of 3
CCND2-AS1	NR_149146.1	n.182+1426G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285901	ENST00000674624.1	n.-171C>T		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000501898.1
CCND2	ENST00000261254.8	c.-171C>T		5_prime_UTR_variant	Exon 1 of 5	1	NM_001759.4	ENSP00000261254.3
ENSG00000285901	ENST00000674624.1	n.-171C>T		5_prime_UTR_variant	Exon 1 of 10			ENSP00000501898.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88116 AN: 151860 Hom.: 25742 Cov.: 31

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.579 AC: 295474 AN: 509928 Hom.: 86416 Cov.: 6 AF XY: 0.575 AC XY: 153040 AN XY: 266150

African (AFR) AF: 0.555 AC: 7428 AN: 13394

American (AMR) AF: 0.686 AC: 12792 AN: 18654

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 8830 AN: 13984

East Asian (EAS) AF: 0.633 AC: 19742 AN: 31180

South Asian (SAS) AF: 0.481 AC: 22831 AN: 47452

European-Finnish (FIN) AF: 0.541 AC: 16289 AN: 30088

Middle Eastern (MID) AF: 0.609 AC: 1276 AN: 2094

European-Non Finnish (NFE) AF: 0.583 AC: 189541 AN: 325014

Other (OTH) AF: 0.597 AC: 16745 AN: 28068

GnomAD4 genome AF: 0.580 AC: 88219 AN: 151978 Hom.: 25784 Cov.: 31 AF XY: 0.581 AC XY: 43193 AN XY: 74324

African (AFR) AF: 0.557 AC: 23087 AN: 41428

American (AMR) AF: 0.667 AC: 10194 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2167 AN: 3470

East Asian (EAS) AF: 0.707 AC: 3642 AN: 5150

South Asian (SAS) AF: 0.461 AC: 2217 AN: 4806

European-Finnish (FIN) AF: 0.544 AC: 5751 AN: 10578

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39061 AN: 67948

Other (OTH) AF: 0.603 AC: 1273 AN: 2112

Alfa AF: 0.594 Hom.: 29595

Bravo AF: 0.599

Asia WGS AF: 0.617 AC: 2147 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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.58
PhyloP100		1.9
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs1049606; hg19: chr12-4383036; COSMIC: COSV54222306; COSMIC: COSV54222306;