rs763292905

Variant names:

• chr22-50519210-A-C
• rs763292905
• NM_152299.4:c.751A>C

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.751A>C​(p.Met251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,458 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NCAPH2 NM_152299.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.930
• Publications: 1 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=0.049316674).

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.751A>C	p.Met251Leu	missense	Exon 9 of 20	NP_689512.2	Q6IBW4-1
	NCAPH2	NM_001185011.2		c.751A>C	p.Met251Leu	missense	Exon 9 of 20	NP_001171940.1	Q6IBW4-4
	NCAPH2	NM_014551.5		c.751A>C	p.Met251Leu	missense	Exon 9 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.751A>C	p.Met251Leu	missense	Exon 9 of 20	ENSP00000410088.2	Q6IBW4-1
	NCAPH2	ENST00000299821.15	TSL:1	c.751A>C	p.Met251Leu	missense	Exon 9 of 20	ENSP00000299821.11	Q6IBW4-4
	NCAPH2	ENST00000395698.7	TSL:1	c.751A>C	p.Met251Leu	missense	Exon 9 of 9	ENSP00000379050.3	Q6IBW4-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000833 AC: 2 AN: 239998 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458458 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 725238

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000451 AC: 2 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111096

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.043
DANN	Benign	0.59
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.090	N
PhyloP100		-0.93
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.0070
Sift	Benign	0.72	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.40		Gain of catalytic residue at M251 (P = 0.034)
MVP		0.082
MPC		0.10
ClinPred		0.025	T
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.12
Mutation Taster		=95/5	polymorphism

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: rs763292905; hg19: chr22-50957639;