rs1555141158

Positions:

• chr12-6531078-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_014865.4(NCAPD2):​c.4120+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCAPD2 NM_014865.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9870
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.82

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.036852118 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of -9, new splice context is: ccaGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-6531078-T-C is Pathogenic according to our data. Variant chr12-6531078-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 524202.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCAPD2	NM_014865.4	c.4120+2T>C		splice_donor_variant, intron_variant		ENST00000315579.10	NP_055680.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCAPD2	ENST00000315579.10	c.4120+2T>C		splice_donor_variant, intron_variant		1	NM_014865.4	ENSP00000325017.5
NCAPD2	ENST00000539084.5	n.*3815+2T>C		splice_donor_variant, intron_variant		2		ENSP00000438495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 21, primary, autosomal recessive Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 12, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555141158; hg19: chr12-6640244;