rs1675126

Positions:

• chr11-62138902-T-C
• chr11-62138902-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001040694.2(INCENP):​c.1188T>C​(p.Asn396=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,613,082 control chromosomes in the GnomAD database, including 639,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59570 hom., cov: 33)
  • Exomes 𝑓: 0.89 (580142 hom.)
• Consequence: INCENP NM_001040694.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.62

Genes affected

INCENP (HGNC:6058): (inner centromere protein) In mammalian cells, 2 broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger,' or transiently interacting, proteins (reviewed by Choo, 1997). The constitutive proteins include CENPA (centromere protein A; MIM 117139), CENPB (MIM 117140), CENPC1 (MIM 117141), and CENPD (MIM 117142). The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle (Earnshaw and Mackay, 1994 [PubMed 8088460]). These include CENPE (MIM 117143); MCAK (MIM 604538); KID (MIM 603213); cytoplasmic dynein (e.g., MIM 600112); CliPs (e.g., MIM 179838); and CENPF/mitosin (MIM 600236). The inner centromere proteins (INCENPs) (Earnshaw and Cooke, 1991 [PubMed 1860899]), the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis (Cutts et al., 1999 [PubMed 10369859]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-62138902-T-C is Benign according to our data. Variant chr11-62138902-T-C is described in ClinVar as [Benign]. Clinvar id is 1261519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INCENP	NM_001040694.2	c.1188T>C	p.Asn396=	synonymous_variant	7/19	ENST00000394818.8	NP_001035784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INCENP	ENST00000394818.8	c.1188T>C	p.Asn396=	synonymous_variant	7/19	1	NM_001040694.2	ENSP00000378295	P2
INCENP	ENST00000278849.4	c.1188T>C	p.Asn396=	synonymous_variant	7/18	5		ENSP00000278849	A2
INCENP	ENST00000528375.1	n.157T>C		non_coding_transcript_exon_variant	4/8	3

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133634 AN: 152082 Hom.: 59517 Cov.: 33

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.906

GnomAD3 exomes AF: 0.842 AC: 211370 AN: 251046 Hom.: 91209 AF XY: 0.839 AC XY: 113950 AN XY: 135738

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.950

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.745

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.888

GnomAD4 exome AF: 0.886 AC: 1294621 AN: 1460880 Hom.: 580142 Cov.: 39 AF XY: 0.882 AC XY: 641334 AN XY: 726814

Gnomad4 AFR exome AF: 0.907

Gnomad4 AMR exome AF: 0.898

Gnomad4 ASJ exome AF: 0.947

Gnomad4 EAS exome AF: 0.442

Gnomad4 SAS exome AF: 0.748

Gnomad4 FIN exome AF: 0.751

Gnomad4 NFE exome AF: 0.917

Gnomad4 OTH exome AF: 0.878

GnomAD4 genome AF: 0.879 AC: 133746 AN: 152202 Hom.: 59570 Cov.: 33 AF XY: 0.866 AC XY: 64438 AN XY: 74394

Gnomad4 AFR AF: 0.904

Gnomad4 AMR AF: 0.929

Gnomad4 ASJ AF: 0.945

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.719

Gnomad4 FIN AF: 0.730

Gnomad4 NFE AF: 0.912

Gnomad4 OTH AF: 0.906

Alfa AF: 0.914 Hom.: 77898

Bravo AF: 0.894

Asia WGS AF: 0.652 AC: 2271 AN: 3478

EpiCase AF: 0.922

EpiControl AF: 0.925

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.11
DANN	Benign	0.23

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: rs1675126; hg19: chr11-61906374; COSMIC: COSV53913818; COSMIC: COSV53913818;