11-62128743-G-A

Position:

• chr11-62128743-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040694.2(INCENP):​c.141-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,534,002 control chromosomes in the GnomAD database, including 305,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23734 hom., cov: 33)
  • Exomes 𝑓: 0.62 (281374 hom.)
• Consequence: INCENP NM_001040694.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.932

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-62128743-G-A is Benign according to our data. Variant chr11-62128743-G-A is described in ClinVar as [Benign]. Clinvar id is 1242936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INCENP	NM_001040694.2	c.141-27G>A		intron_variant		ENST00000394818.8	NP_001035784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INCENP	ENST00000394818.8	c.141-27G>A		intron_variant		1	NM_001040694.2	ENSP00000378295.3
INCENP	ENST00000528037.1	n.305-27G>A		intron_variant		1
INCENP	ENST00000278849.4	c.141-27G>A		intron_variant		5		ENSP00000278849.4
INCENP	ENST00000533896.5	c.141-27G>A		intron_variant		4		ENSP00000433100.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80388 AN: 151960 Hom.: 23736 Cov.: 33

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.577

GnomAD3 exomes AF: 0.510 AC: 127872 AN: 250896 Hom.: 38322 AF XY: 0.518 AC XY: 70193 AN XY: 135604

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.619 AC: 854844 AN: 1381924 Hom.: 281374 Cov.: 21 AF XY: 0.611 AC XY: 422952 AN XY: 691972

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.717

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.598

GnomAD4 genome AF: 0.529 AC: 80406 AN: 152078 Hom.: 23734 Cov.: 33 AF XY: 0.516 AC XY: 38369 AN XY: 74322

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.275

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.573

Alfa AF: 0.637 Hom.: 24430

Bravo AF: 0.510

Asia WGS AF: 0.238 AC: 835 AN: 3478

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	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.057
DANN	Benign	0.46

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: rs1792946; hg19: chr11-61896215;