12-6514774-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014865.4(NCAPD2):c.841G>A(p.Glu281Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NCAPD2 NM_014865.4 missense, splice_region
• Scores: Splicing: ADA: 0.9875
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAPD2	NM_014865.4	c.841G>A	p.Glu281Lys	missense_variant, splice_region_variant	9/32	ENST00000315579.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAPD2	ENST00000315579.10	c.841G>A	p.Glu281Lys	missense_variant, splice_region_variant	9/32	1	NM_014865.4	P1
NCAPD2	ENST00000382457.8	c.457G>A	p.Glu153Lys	missense_variant, splice_region_variant	6/21	5
NCAPD2	ENST00000545732.1	n.353G>A		splice_region_variant, non_coding_transcript_exon_variant	3/4	5
NCAPD2	ENST00000539084.5	c.*536G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	8/31	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.841G>A (p.E281K) alteration is located in exon 9 (coding exon 8) of the NCAPD2 gene. This alteration results from a G to A substitution at nucleotide position 841, causing the glutamic acid (E) at amino acid position 281 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.61		Gain of methylation at E281 (P = 0.0051);.;
MVP		0.60
MPC		0.79
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6623940;