10-60177246-C-T

Variant names:

• chr10-60177246-C-T
• rs12355908
• NM_020987.5:c.2185-4060G>A

Variant summary

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

The NM_020987.5(ANK3):​c.2185-4060G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,090 control chromosomes in the GnomAD database, including 3,391 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 0.19 (3391 hom., cov: 32)
• Consequence: ANK3 NM_020987.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_020987.5	c.2185-4060G>A		intron_variant	Intron 18 of 43	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.2134-4060G>A		intron_variant	Intron 18 of 43		NP_001191333.1
ANK3	NM_001320874.2	c.2185-4060G>A		intron_variant	Intron 18 of 42		NP_001307803.1
ANK3	NM_001204403.2	c.2167-4060G>A		intron_variant	Intron 19 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.2185-4060G>A		intron_variant	Intron 18 of 43	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29636 AN: 151970 Hom.: 3390 Cov.: 32

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.196

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.195 AC: 29645 AN: 152090 Hom.: 3391 Cov.: 32 AF XY: 0.194 AC XY: 14424 AN XY: 74366

African (AFR) AF: 0.0843 AC: 3498 AN: 41518

American (AMR) AF: 0.218 AC: 3335 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 799 AN: 3468

East Asian (EAS) AF: 0.147 AC: 758 AN: 5164

South Asian (SAS) AF: 0.159 AC: 766 AN: 4818

European-Finnish (FIN) AF: 0.230 AC: 2429 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17243 AN: 67972

Other (OTH) AF: 0.197 AC: 413 AN: 2098

Alfa AF: 0.233 Hom.: 3500

Bravo AF: 0.190

Asia WGS AF: 0.168 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.4
DANN	Benign	0.68
PhyloP100		-0.30
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: rs12355908; hg19: chr10-61937004;