chr2-112738977-C-T

Position:

• chr2-112738977-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152515.5(CKAP2L):​c.2084G>A​(p.Arg695Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,184 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (116 hom.)
• Consequence: CKAP2L NM_152515.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.276

Genes affected

CKAP2L (HGNC:26877): (cytoskeleton associated protein 2 like) The protein encoded by this gene is thought to be a mitotic spindle protein important to neural stem or progenitor cells. Mutations in this gene have been associated with spindle organization defects, including mitotic spindle defects, lagging chromosomes, and chromatin bridges. There is evidence that mutations in this gene are associated with Filippi syndrome, characterized by growth defects, microcephaly, intellectual disability, facial feature defects, and syndactyly. There is a pseudogene of this gene on chromosome 20. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

NT5DC4 (HGNC:27678): (5'-nucleotidase domain containing 4) Predicted to enable 5'-nucleotidase activity. Predicted to be involved in dephosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033853948).
• BP6: Variant 2-112738977-C-T is Benign according to our data. Variant chr2-112738977-C-T is described in ClinVar as [Benign]. Clinvar id is 790255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-112738977-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00833 (1268/152310) while in subpopulation NFE AF= 0.0133 (907/68038). AF 95% confidence interval is 0.0126. There are 9 homozygotes in gnomad4. There are 593 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CKAP2L	NM_152515.5	c.2084G>A	p.Arg695Gln	missense_variant	9/9	ENST00000302450.11
NT5DC4	NM_001393655.1	c.*41C>T		3_prime_UTR_variant	17/17	ENST00000688554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CKAP2L	ENST00000302450.11	c.2084G>A	p.Arg695Gln	missense_variant	9/9	1	NM_152515.5	P1
NT5DC4	ENST00000688554.1	c.*41C>T		3_prime_UTR_variant	17/17		NM_001393655.1

Frequencies

GnomAD3 genomes AF: 0.00833 AC: 1268 AN: 152192 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00878 AC: 2208 AN: 251462 Hom.: 14 AF XY: 0.00871 AC XY: 1184 AN XY: 135904

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0113 AC: 16482 AN: 1461874 Hom.: 116 Cov.: 31 AF XY: 0.0109 AC XY: 7963 AN XY: 727248

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00899

GnomAD4 genome AF: 0.00833 AC: 1268 AN: 152310 Hom.: 9 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74478

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0105 Hom.: 18

Bravo AF: 0.00714

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00897 AC: 1089

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CKAP2L: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0045	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.66	N;N;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.11
Sift	Benign	0.095	T
Sift4G	Benign	0.098	T
Polyphen		0.93	P
Vest4		0.081
MVP		0.25
MPC		0.14
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.044
gMVP		0.21

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: rs116342308; hg19: chr2-113496554;