chr3-46979634-A-G

Variant names:

• chr3-46979634-A-G
• rs13062681
• NM_144716.6:c.-73+2298T>C

Variant summary

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

The NM_144716.6(CCDC12):​c.-73+2298T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 305,436 control chromosomes in the GnomAD database, including 44,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19812 hom., cov: 33)
  • Exomes 𝑓: 0.57 (24822 hom.)
• Consequence: CCDC12 NM_144716.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.71
• Publications: 8 publications found

Genes affected

CCDC12 (HGNC:28332): (coiled-coil domain containing 12) Predicted to be part of U2-type spliceosomal complex and post-mRNA release spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

NBEAL2 (HGNC:31928): (neurobeachin like 2) The protein encoded by this gene contains a beige and Chediak-Higashi (BEACH) domain and multiple WD40 domains, and may play a role in megakaryocyte alpha-granule biogenesis. Mutations in this gene are a cause of gray platelet syndrome. [provided by RefSeq, Dec 2011]

NBEAL2 Gene-Disease associations (from GenCC):

• gray platelet syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-46979634-A-G is Benign according to our data. Variant chr3-46979634-A-G is described in ClinVar as Benign. ClinVar VariationId is 1248264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144716.6. 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
	CCDC12	NM_144716.6		c.-73+2298T>C		intron	N/A	NP_653317.2	J3KR35
	NBEAL2	NM_015175.3	MANE Select	c.-228A>G		upstream_gene	N/A	NP_055990.1	Q6ZNJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC12	ENST00000292314.6	TSL:5	c.-73+2298T>C		intron	N/A	ENSP00000292314.2	J3KR35
	CCDC12	ENST00000425441.5	TSL:5	c.-215+2298T>C		intron	N/A	ENSP00000416263.2	Q8WUD4
	CCDC12	ENST00000446836.5	TSL:3	c.-112+2298T>C		intron	N/A	ENSP00000387490.2	C9JUN5

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74589 AN: 151926 Hom.: 19788 Cov.: 33

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.566 AC: 86808 AN: 153390 Hom.: 24822 Cov.: 0 AF XY: 0.567 AC XY: 44750 AN XY: 78986

African (AFR) AF: 0.292 AC: 1142 AN: 3912

American (AMR) AF: 0.559 AC: 2435 AN: 4356

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 2848 AN: 5280

East Asian (EAS) AF: 0.541 AC: 8070 AN: 14916

South Asian (SAS) AF: 0.556 AC: 804 AN: 1446

European-Finnish (FIN) AF: 0.604 AC: 8693 AN: 14384

Middle Eastern (MID) AF: 0.462 AC: 373 AN: 808

European-Non Finnish (NFE) AF: 0.581 AC: 57269 AN: 98648

Other (OTH) AF: 0.537 AC: 5174 AN: 9640

GnomAD4 genome AF: 0.491 AC: 74646 AN: 152046 Hom.: 19812 Cov.: 33 AF XY: 0.492 AC XY: 36582 AN XY: 74334

African (AFR) AF: 0.283 AC: 11749 AN: 41498

American (AMR) AF: 0.536 AC: 8199 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1903 AN: 3470

East Asian (EAS) AF: 0.532 AC: 2731 AN: 5132

South Asian (SAS) AF: 0.537 AC: 2593 AN: 4826

European-Finnish (FIN) AF: 0.614 AC: 6499 AN: 10584

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39396 AN: 67942

Other (OTH) AF: 0.504 AC: 1060 AN: 2104

Alfa AF: 0.403 Hom.: 1230

Bravo AF: 0.475

Asia WGS AF: 0.586 AC: 2035 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.4
DANN	Benign	0.72
PhyloP100		-3.7
PromoterAI		0.0048	Neutral
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: rs13062681; hg19: chr3-47021124;