NM_020987.5:c.2948+2553G>C

Variant names:

• chr10-60111672-C-G
• rs10821675
• NM_020987.5:c.2948+2553G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020987.5(ANK3):​c.2948+2553G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 446,230 control chromosomes in the GnomAD database, including 111,184 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39775 hom., cov: 31)
  • Exomes 𝑓: 0.69 (71409 hom.)
• Consequence: ANK3 NM_020987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 3 publications found

Genes affected

ANK3 (HGNC:494): (ankyrin 3) Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ANK3 Gene-Disease associations (from GenCC):

• intellectual disability-hypotonia-spasticity-sleep disorder syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• intellectual disability

  Inheritance: AR, AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020987.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	NM_020987.5	MANE Select	c.2948+2553G>C		intron	N/A	NP_066267.2
	ANK3	NM_001204404.2		c.2951+2553G>C		intron	N/A	NP_001191333.1
	ANK3	NM_001320874.2		c.2948+2553G>C		intron	N/A	NP_001307803.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.2948+2553G>C		intron	N/A	ENSP00000280772.1
	ANK3	ENST00000373827.6	TSL:1	c.2930+2553G>C		intron	N/A	ENSP00000362933.2
	ANK3	ENST00000355288.6	TSL:1	c.350+2553G>C		intron	N/A	ENSP00000347436.2

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109361 AN: 151878 Hom.: 39745 Cov.: 31

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.717

GnomAD4 exome AF: 0.693 AC: 203977 AN: 294234 Hom.: 71409 AF XY: 0.690 AC XY: 115735 AN XY: 167852

African (AFR) AF: 0.796 AC: 6506 AN: 8174

American (AMR) AF: 0.795 AC: 20663 AN: 26000

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 7589 AN: 10454

East Asian (EAS) AF: 0.934 AC: 8553 AN: 9156

South Asian (SAS) AF: 0.673 AC: 38542 AN: 57284

European-Finnish (FIN) AF: 0.670 AC: 8128 AN: 12140

Middle Eastern (MID) AF: 0.688 AC: 1657 AN: 2408

European-Non Finnish (NFE) AF: 0.663 AC: 102697 AN: 154838

Other (OTH) AF: 0.700 AC: 9642 AN: 13780

GnomAD4 genome AF: 0.720 AC: 109448 AN: 151996 Hom.: 39775 Cov.: 31 AF XY: 0.719 AC XY: 53438 AN XY: 74302

African (AFR) AF: 0.799 AC: 33153 AN: 41472

American (AMR) AF: 0.734 AC: 11211 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2557 AN: 3468

East Asian (EAS) AF: 0.924 AC: 4784 AN: 5180

South Asian (SAS) AF: 0.680 AC: 3282 AN: 4826

European-Finnish (FIN) AF: 0.666 AC: 7004 AN: 10516

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45154 AN: 67954

Other (OTH) AF: 0.720 AC: 1521 AN: 2112

Alfa AF: 0.604 Hom.: 1695

Bravo AF: 0.731

Asia WGS AF: 0.788 AC: 2737 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.51
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10821675; hg19: chr10-61871430;