chr22-50517802-C-G

Variant names:

• chr22-50517802-C-G
• rs138318301
• NM_152299.4:c.413C>G

Variant summary

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

The NM_152299.4(NCAPH2):​c.413C>G​(p.Thr138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T138M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NCAPH2 NM_152299.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.223
• Publications: 0 publications found

Genes affected

NCAPH2 (HGNC:25071): (non-SMC condensin II complex subunit H2) This gene encodes one of the non-SMC subunits of the condensin II complex. This complex plays an essential role in mitotic chromosome assembly. Alternate splicing of this gene results in multiple transcript variants.[provided by RefSeq, May 2010]

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 (MetaRNN=0.04410082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152299.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPH2	NM_152299.4	MANE Select	c.413C>G	p.Thr138Arg	missense	Exon 5 of 20	NP_689512.2	Q6IBW4-1
	NCAPH2	NM_001185011.2		c.413C>G	p.Thr138Arg	missense	Exon 5 of 20	NP_001171940.1	Q6IBW4-4
	NCAPH2	NM_014551.5		c.413C>G	p.Thr138Arg	missense	Exon 5 of 9	NP_055366.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPH2	ENST00000420993.7	TSL:1 MANE Select	c.413C>G	p.Thr138Arg	missense	Exon 5 of 20	ENSP00000410088.2	Q6IBW4-1
	NCAPH2	ENST00000299821.15	TSL:1	c.413C>G	p.Thr138Arg	missense	Exon 5 of 20	ENSP00000299821.11	Q6IBW4-4
	NCAPH2	ENST00000395698.7	TSL:1	c.413C>G	p.Thr138Arg	missense	Exon 5 of 9	ENSP00000379050.3	Q6IBW4-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461514 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727018

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.72
DANN	Benign	0.49
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.22
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.052
Sift	Benign	0.49	T
Sift4G	Benign	0.54	T
Polyphen		0.14	B
Vest4		0.18
MutPred		0.46		Loss of phosphorylation at T138 (P = 0.0281)
MVP		0.068
MPC		0.16
ClinPred		0.039	T
GERP RS		-1.1
Varity_R		0.023
gMVP		0.12
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138318301; hg19: chr22-50956231;