12-6495106-C-A

Position:

chr12-6495106-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_014865.4(NCAPD2):c.8C>A(p.Pro3His) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

NCAPD2
NM_014865.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.91

Variant links:

Genes affected

NCAPD2 (HGNC:24305): (non-SMC condensin I complex subunit D2) Enables histone binding activity. Involved in mitotic chromosome condensation. Located in condensed chromosome; cytosol; and nucleoplasm. Part of condensin complex. Colocalizes with cytoplasm and nuclear chromosome. Implicated in primary autosomal recessive microcephaly. [provided by Alliance of Genome Resources, Apr 2022]

NCAPD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0066705346).

BP6

Variant 12-6495106-C-A is Benign according to our data. Variant chr12-6495106-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2225476.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00105 (160/152274) while in subpopulation AFR AF= 0.00356 (148/41556). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCAPD2	NM_014865.4 linkuse as main transcript	c.8C>A	p.Pro3His	missense_variant	2/32	ENST00000315579.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCAPD2	ENST00000315579.10 linkuse as main transcript	c.8C>A	p.Pro3His	missense_variant	2/32	1	NM_014865.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251440

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00385

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152274

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00356

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000974

Hom.:

Bravo

AF:

0.00107

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000379

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NCAPD2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0095

T;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.50

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

N;.;.

MutationTaster

Benign

0.56

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.77

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0030

D;D;T

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.51

MVP

0.71

MPC

0.78

ClinPred

0.052

GERP RS

5.8

Varity_R

0.14

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over