11-62128269-A-G

Position:

• chr11-62128269-A-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.108A>G​(p.Glu36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,613,518 control chromosomes in the GnomAD database, including 325,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (24211 hom., cov: 33)
  • Exomes 𝑓: 0.62 (301687 hom.)
• Consequence: INCENP NM_001040694.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22

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=-0.71).
• BP6: Variant 11-62128269-A-G is Benign according to our data. Variant chr11-62128269-A-G is described in ClinVar as [Benign]. Clinvar id is 1279221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INCENP	NM_001040694.2	c.108A>G	p.Glu36=	synonymous_variant	2/19	ENST00000394818.8	NP_001035784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INCENP	ENST00000394818.8	c.108A>G	p.Glu36=	synonymous_variant	2/19	1	NM_001040694.2	ENSP00000378295	P2
INCENP	ENST00000528037.1	n.272A>G		non_coding_transcript_exon_variant	2/5	1
INCENP	ENST00000278849.4	c.108A>G	p.Glu36=	synonymous_variant	2/18	5		ENSP00000278849	A2
INCENP	ENST00000533896.5	c.108A>G	p.Glu36=	synonymous_variant	2/4	4		ENSP00000433100

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81342 AN: 151966 Hom.: 24212 Cov.: 33

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.582

GnomAD3 exomes AF: 0.513 AC: 128943 AN: 251192 Hom.: 38813 AF XY: 0.521 AC XY: 70716 AN XY: 135790

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.309

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.624 AC: 912335 AN: 1461434 Hom.: 301687 Cov.: 48 AF XY: 0.617 AC XY: 448509 AN XY: 727040

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.717

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.614

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.535 AC: 81360 AN: 152084 Hom.: 24211 Cov.: 33 AF XY: 0.522 AC XY: 38838 AN XY: 74342

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.579

Alfa AF: 0.658 Hom.: 40697

Bravo AF: 0.517

Asia WGS AF: 0.247 AC: 865 AN: 3478

EpiCase AF: 0.690

EpiControl AF: 0.691

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 04, 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	-0.71
CADD	Benign	9.2
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1675131; hg19: chr11-61895741; COSMIC: COSV53915302; COSMIC: COSV53915302;