12-6528679-T-C

Variant names:

• chr12-6528679-T-C
• rs2072374
• NM_014865.4:c.3300T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014865.4(NCAPD2):​c.3300T>C​(p.Arg1100Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,607,368 control chromosomes in the GnomAD database, including 429,779 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47652 hom., cov: 31)
  • Exomes 𝑓: 0.72 (382127 hom.)
• Consequence: NCAPD2 NM_014865.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001095
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.690
• Publications: 28 publications found

Genes affected

NCAPD2 (HGNC:24305): (non-SMC condensin I complex subunit D2) Enables histone binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytosol; and nucleoplasm. Part of condensin complex. Colocalizes with cytoplasm and nuclear chromosome. Implicated in primary autosomal recessive microcephaly. [provided by Alliance of Genome Resources, Apr 2022]

GAPDH-DT (HGNC:55492): (GAPDH divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-6528679-T-C is Benign according to our data. Variant chr12-6528679-T-C is described in ClinVar as Benign. ClinVar VariationId is 1321846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAPD2	NM_014865.4	c.3300T>C	p.Arg1100Arg	splice_region_variant, synonymous_variant	Exon 26 of 32	ENST00000315579.10	NP_055680.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAPD2	ENST00000315579.10	c.3300T>C	p.Arg1100Arg	splice_region_variant, synonymous_variant	Exon 26 of 32	1	NM_014865.4	ENSP00000325017.5

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119244 AN: 151948 Hom.: 47597 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.745 AC: 186624 AN: 250596 AF XY: 0.733

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.862

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.667

Gnomad FIN exome AF: 0.750

Gnomad NFE exome AF: 0.711

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.723 AC: 1052289 AN: 1455300 Hom.: 382127 Cov.: 56 AF XY: 0.721 AC XY: 520689 AN XY: 722480

African (AFR) AF: 0.955 AC: 31857 AN: 33356

American (AMR) AF: 0.857 AC: 38239 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 18455 AN: 26078

East Asian (EAS) AF: 0.664 AC: 26225 AN: 39486

South Asian (SAS) AF: 0.681 AC: 58712 AN: 86178

European-Finnish (FIN) AF: 0.750 AC: 39904 AN: 53180

Middle Eastern (MID) AF: 0.694 AC: 3990 AN: 5750

European-Non Finnish (NFE) AF: 0.715 AC: 791121 AN: 1106584

Other (OTH) AF: 0.729 AC: 43786 AN: 60082

GnomAD4 genome AF: 0.785 AC: 119360 AN: 152068 Hom.: 47652 Cov.: 31 AF XY: 0.784 AC XY: 58287 AN XY: 74316

African (AFR) AF: 0.944 AC: 39208 AN: 41520

American (AMR) AF: 0.797 AC: 12179 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2473 AN: 3472

East Asian (EAS) AF: 0.677 AC: 3503 AN: 5174

South Asian (SAS) AF: 0.672 AC: 3228 AN: 4802

European-Finnish (FIN) AF: 0.751 AC: 7939 AN: 10566

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.713 AC: 48476 AN: 67950

Other (OTH) AF: 0.757 AC: 1595 AN: 2108

Alfa AF: 0.733 Hom.: 193580

Bravo AF: 0.798

Asia WGS AF: 0.762 AC: 2649 AN: 3478

EpiCase AF: 0.705

EpiControl AF: 0.691

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 21, primary, autosomal recessive Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		0.69
Mutation Taster		=74/26	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.016
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: rs2072374; hg19: chr12-6637845; COSMIC: COSV59701640; COSMIC: COSV59701640;