Genetic Variant NM_015341.5:c.728C>G (chr2-96351838-C-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.82

Publications

0 publications found

Variant links:

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

NCAPH links:

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ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015341.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NCAPH	NM_015341.5	MANE Select	c.728C>G	p.Pro243Arg	missense	Exon 7 of 18	NP_056156.2
NCAPH	NM_001281710.2		c.695C>G	p.Pro232Arg	missense	Exon 7 of 18	NP_001268639.1
NCAPH	NM_001281711.2		c.656C>G	p.Pro219Arg	missense	Exon 7 of 18	NP_001268640.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCAPH	ENST00000240423.9	TSL:1 MANE Select	c.728C>G	p.Pro243Arg	missense	Exon 7 of 18	ENSP00000240423.4	Q15003-1
NCAPH	ENST00000435975.5	TSL:1	c.695C>G	p.Pro232Arg	missense	Exon 7 of 14	ENSP00000405237.1	C9J470
NCAPH	ENST00000477409.1	TSL:1	n.685C>G		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.035

MutationAssessor

Pathogenic

3.5

PhyloP100

5.8

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.97

MutPred

0.89

Gain of solvent accessibility (P = 0.0171)

MVP

0.90

MPC

0.76

ClinPred

0.99

GERP RS

5.0

Varity_R

0.86

gMVP

0.75

Mutation Taster

=8/92

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over