NM_014865.4:c.1920C>A

Variant names:

• chr12-6522003-C-A
• rs917634
• NM_014865.4:c.1920C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014865.4(NCAPD2):​c.1920C>A​(p.Ile640Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,514 control chromosomes in the GnomAD database, including 175,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19657 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155907 hom.)
• Consequence: NCAPD2 NM_014865.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.27
• Publications: 45 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]

NCAPD2 Gene-Disease associations (from GenCC):

• microcephaly 21, primary, autosomal recessive

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-6522003-C-A is Benign according to our data. Variant chr12-6522003-C-A is described in ClinVar as Benign. ClinVar VariationId is 1238523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014865.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD2	NM_014865.4	MANE Select	c.1920C>A	p.Ile640Ile	synonymous	Exon 15 of 32	NP_055680.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD2	ENST00000315579.10	TSL:1 MANE Select	c.1920C>A	p.Ile640Ile	synonymous	Exon 15 of 32	ENSP00000325017.5
	NCAPD2	ENST00000382457.8	TSL:5	c.1536C>A	p.Ile512Ile	synonymous	Exon 12 of 21	ENSP00000371895.4
	NCAPD2	ENST00000538600.1	TSL:3	n.84C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76541 AN: 151920 Hom.: 19638 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.526

GnomAD2 exomes AF: 0.488 AC: 122716 AN: 251428 AF XY: 0.476

Gnomad AFR exome AF: 0.587

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.566

Gnomad FIN exome AF: 0.450

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.459 AC: 671004 AN: 1461476 Hom.: 155907 Cov.: 42 AF XY: 0.455 AC XY: 331177 AN XY: 727078

African (AFR) AF: 0.598 AC: 20021 AN: 33472

American (AMR) AF: 0.607 AC: 27144 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13268 AN: 26132

East Asian (EAS) AF: 0.518 AC: 20567 AN: 39694

South Asian (SAS) AF: 0.375 AC: 32379 AN: 86250

European-Finnish (FIN) AF: 0.452 AC: 24118 AN: 53412

Middle Eastern (MID) AF: 0.479 AC: 2764 AN: 5768

European-Non Finnish (NFE) AF: 0.452 AC: 501968 AN: 1111638

Other (OTH) AF: 0.477 AC: 28775 AN: 60388

GnomAD4 genome AF: 0.504 AC: 76592 AN: 152038 Hom.: 19657 Cov.: 32 AF XY: 0.502 AC XY: 37319 AN XY: 74314

African (AFR) AF: 0.585 AC: 24268 AN: 41476

American (AMR) AF: 0.551 AC: 8436 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3468

East Asian (EAS) AF: 0.558 AC: 2884 AN: 5170

South Asian (SAS) AF: 0.378 AC: 1825 AN: 4822

European-Finnish (FIN) AF: 0.450 AC: 4754 AN: 10560

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31028 AN: 67930

Other (OTH) AF: 0.521 AC: 1099 AN: 2110

Alfa AF: 0.478 Hom.: 64587

Bravo AF: 0.521

Asia WGS AF: 0.505 AC: 1756 AN: 3478

EpiCase AF: 0.468

EpiControl AF: 0.457

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

May 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.0
DANN	Benign	0.61
PhyloP100		1.3
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: rs917634; hg19: chr12-6631169; COSMIC: COSV59698353; COSMIC: COSV59698353;