dbSNP rs917634: NCAPD2:p.Ile640Ile (chr12-6522003-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014865.4(NCAPD2):c.1920C>A(p.Ile640Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,613,514 control chromosomes in the GnomAD database, including 175,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19657 hom., cov: 32)

Exomes 𝑓: 0.46 ( 155907 hom. )

Consequence

NCAPD2
NM_014865.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.27

Publications

45 publications found

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 Gene-Disease associations (from GenCC):

microcephaly 21, primary, autosomal recessive
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

NCAPD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 12-6522003-C-A is Benign according to our data. Variant chr12-6522003-C-A is described in ClinVar as Benign. ClinVar VariationId is 1238523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCAPD2	NM_014865.4 link	c.1920C>A	p.Ile640Ile	synonymous_variant	Exon 15 of 32	ENST00000315579.10	NP_055680.3	Q15021B3KY03B3KMS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCAPD2	ENST00000315579.10 link	c.1920C>A	p.Ile640Ile	synonymous_variant	Exon 15 of 32	1	NM_014865.4	ENSP00000325017.5		Q15021

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76541

AN:

151920

Hom.:

19638

Cov.:

show subpopulations

Gnomad AFR

AF:

0.586

Gnomad AMI

AF:

0.455

Gnomad AMR

AF:

0.551

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.378

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.526

GnomAD2 exomes

AF:

0.488

AC:

122716

AN:

251428

AF XY:

0.476

show subpopulations

Gnomad AFR exome

AF:

0.587

Gnomad AMR exome

AF:

0.610

Gnomad ASJ exome

AF:

0.500

Gnomad EAS exome

AF:

0.566

Gnomad FIN exome

AF:

0.450

Gnomad NFE exome

AF:

0.459

Gnomad OTH exome

AF:

0.481

GnomAD4 exome

AF:

0.459

AC:

671004

AN:

1461476

Hom.:

155907

Cov.:

AF XY:

0.455

AC XY:

331177

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.598

AC:

20021

AN:

33472

American (AMR)

AF:

0.607

AC:

27144

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.508

AC:

13268

AN:

26132

East Asian (EAS)

AF:

0.518

AC:

20567

AN:

39694

South Asian (SAS)

AF:

0.375

AC:

32379

AN:

86250

European-Finnish (FIN)

AF:

0.452

AC:

24118

AN:

53412

Middle Eastern (MID)

AF:

0.479

AC:

2764

AN:

5768

European-Non Finnish (NFE)

AF:

0.452

AC:

501968

AN:

1111638

Other (OTH)

AF:

0.477

AC:

28775

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19154

38309

57463

76618

95772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15162

30324

45486

60648

75810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.504

AC:

76592

AN:

152038

Hom.:

19657

Cov.:

AF XY:

0.502

AC XY:

37319

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.585

AC:

24268

AN:

41476

American (AMR)

AF:

0.551

AC:

8436

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1753

AN:

3468

East Asian (EAS)

AF:

0.558

AC:

2884

AN:

5170

South Asian (SAS)

AF:

0.378

AC:

1825

AN:

4822

European-Finnish (FIN)

AF:

0.450

AC:

4754

AN:

10560

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.457

AC:

31028

AN:

67930

Other (OTH)

AF:

0.521

AC:

1099

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1929

3858

5786

7715

9644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.478

Hom.:

64587

Bravo

AF:

0.521

Asia WGS

AF:

0.505

AC:

1756

AN:

3478

EpiCase

AF:

0.468

EpiControl

AF:

0.457

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 06, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly 21, primary, autosomal recessive

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.0

(source)

DANN

Benign

0.61

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over