rs1553446603

Variant names:

• chr2-96351838-C-G
• rs1553446603
• NM_015341.5:c.728C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-96351838-C-G
• chr2-96351838-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_015341.5(NCAPH):​c.728C>G​(p.Pro243Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P243L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCAPH NM_015341.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• Publications: 0 publications found

Genes affected

NCAPH (HGNC:1112): (non-SMC condensin I complex subunit H) This gene encodes a member of the barr gene family and a regulatory subunit of the condensin complex. This complex is required for the conversion of interphase chromatin into condensed chromosomes. The protein encoded by this gene is associated with mitotic chromosomes, except during the early phase of chromosome condensation. During interphase, the protein has a distinct punctate nucleolar localization. Alternatively spliced transcript variants encoding different proteins have been described. [provided by RefSeq, Jul 2013]

NCAPH Gene-Disease associations (from GenCC):

• microcephaly 23, primary, autosomal recessive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-96351838-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 524196.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAPH	NM_015341.5	c.728C>G	p.Pro243Arg	missense_variant	Exon 7 of 18	ENST00000240423.9	NP_056156.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAPH	ENST00000240423.9	c.728C>G	p.Pro243Arg	missense_variant	Exon 7 of 18	1	NM_015341.5	ENSP00000240423.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.035	D
MutationAssessor	Pathogenic	3.5	H;.;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;T;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.97
MutPred		0.89		Gain of solvent accessibility (P = 0.0171);.;.;.;.;
MVP		0.90
MPC		0.76
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.75
Mutation Taster		=8/92	disease causing

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: rs1553446603; hg19: chr2-97017576;