12-6522722-G-C

Variant names:

• chr12-6522722-G-C
• rs2072373
• NM_014865.4:c.1955-106G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014865.4(NCAPD2):​c.1955-106G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: NCAPD2 NM_014865.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.843
• Publications: 11 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAPD2	NM_014865.4	c.1955-106G>C		intron_variant	Intron 15 of 31	ENST00000315579.10	NP_055680.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAPD2	ENST00000315579.10	c.1955-106G>C		intron_variant	Intron 15 of 31	1	NM_014865.4	ENSP00000325017.5
NCAPD2	ENST00000382457.8	c.1571-106G>C		intron_variant	Intron 12 of 20	5		ENSP00000371895.4
NCAPD2	ENST00000538600.1	n.119-162G>C		intron_variant	Intron 1 of 2	3
NCAPD2	ENST00000539084.5	n.*1650-106G>C		intron_variant	Intron 14 of 30	2		ENSP00000438495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097716 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 551630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000402 AC: 1 AN: 24904

American (AMR) AF: 0.00 AC: 0 AN: 31644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19088

East Asian (EAS) AF: 0.00 AC: 0 AN: 37576

South Asian (SAS) AF: 0.00 AC: 0 AN: 66230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4810

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 816698

Other (OTH) AF: 0.00 AC: 0 AN: 47308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.7
DANN	Benign	0.62
PhyloP100		0.84

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: rs2072373; hg19: chr12-6631888;