rs1553446603

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015341.5(NCAPH):​c.728C>T​(p.Pro243Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,445,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P243S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: NCAPH NM_015341.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-96351838-C-T is Pathogenic according to our data. 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPH	NM_015341.5	MANE Select	c.728C>T	p.Pro243Leu	missense	Exon 7 of 18	NP_056156.2
	NCAPH	NM_001281710.2		c.695C>T	p.Pro232Leu	missense	Exon 7 of 18	NP_001268639.1
	NCAPH	NM_001281711.2		c.656C>T	p.Pro219Leu	missense	Exon 7 of 18	NP_001268640.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPH	ENST00000240423.9	TSL:1 MANE Select	c.728C>T	p.Pro243Leu	missense	Exon 7 of 18	ENSP00000240423.4	Q15003-1
	NCAPH	ENST00000435975.5	TSL:1	c.695C>T	p.Pro232Leu	missense	Exon 7 of 14	ENSP00000405237.1	C9J470
	NCAPH	ENST00000477409.1	TSL:1	n.685C>T		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445854 Hom.: 0 Cov.: 31 AF XY: 0.00000696 AC XY: 5 AN XY: 718172

African (AFR) AF: 0.00 AC: 0 AN: 32836

American (AMR) AF: 0.00 AC: 0 AN: 40974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 83026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105520

Other (OTH) AF: 0.0000502 AC: 3 AN: 59768

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Microcephaly 23, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.0061	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.92		Loss of catalytic residue at P243 (P = 0.0307)
MVP		0.90
MPC		0.74
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.73
gMVP		0.71
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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;