4-17843357-G-A

Position:

• chr4-17843357-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022346.5(NCAPG):​c.2980G>A​(p.Ala994Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00176 in 1,612,146 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (8 hom.)
• Consequence: NCAPG NM_022346.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

Genes affected

NCAPG (HGNC:24304): (non-SMC condensin I complex subunit G) This gene encodes a subunit of the condensin complex, which is responsible for the condensation and stabilization of chromosomes during mitosis and meiosis. Phosphorylation of the encoded protein activates the condensin complex. There are pseudogenes for this gene on chromosomes 8 and 15. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

LCORL (HGNC:30776): (ligand dependent nuclear receptor corepressor like) This gene encodes a transcription factor that appears to function in spermatogenesis. Polymorphisms in this gene are associated with measures of skeletal frame size and adult height. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NCAPG (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0411686).
• BS2: High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCAPG	NM_022346.5	c.2980G>A	p.Ala994Thr	missense_variant	21/21	ENST00000251496.7	NP_071741.2
LCORL	NM_001394446.1	c.*2531C>T		3_prime_UTR_variant	8/8	ENST00000635767.2	NP_001381375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCAPG	ENST00000251496.7	c.2980G>A	p.Ala994Thr	missense_variant	21/21	1	NM_022346.5	ENSP00000251496.2
LCORL	ENST00000635767	c.*2531C>T		3_prime_UTR_variant	8/8	5	NM_001394446.1	ENSP00000490600.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 275 AN: 251164 Hom.: 1 AF XY: 0.00105 AC XY: 142 AN XY: 135760

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00184 AC: 2681 AN: 1460122 Hom.: 8 Cov.: 30 AF XY: 0.00181 AC XY: 1313 AN XY: 726348

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74318

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00120

EpiControl AF: 0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.2980G>A (p.A994T) alteration is located in exon 21 (coding exon 21) of the NCAPG gene. This alteration results from a G to A substitution at nucleotide position 2980, causing the alanine (A) at amino acid position 994 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0068	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.23
MVP		0.47
MPC		0.20
ClinPred		0.034	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.56

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

Other links and lift over

dbSNP: rs141707867; hg19: chr4-17844980;