rs1938526

Variant names:

• chr10-60540625-A-G
• rs1938526
• ENST00000373827.6:c.96+74561T>C

Variant summary

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

The ENST00000373827.6(ANK3):​c.96+74561T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 151,918 control chromosomes in the GnomAD database, including 1,147 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 0.088 (1147 hom., cov: 32)
• Consequence: ANK3 ENST00000373827.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 47 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANK3	NM_001204404.2	c.63+31840T>C		intron_variant	Intron 1 of 43		NP_001191333.1
ANK3	NM_001204403.2	c.96+74561T>C		intron_variant	Intron 2 of 43		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000373827.6	c.96+74561T>C		intron_variant	Intron 2 of 43	1		ENSP00000362933.2
ANK3	ENST00000503366.6	c.63+31840T>C		intron_variant	Intron 1 of 43	2		ENSP00000425236.1
ANK3	ENST00000510382.1	n.102-32000T>C		intron_variant	Intron 2 of 2	2
ANK3	ENST00000622427.4	n.63+31840T>C		intron_variant	Intron 1 of 32	2		ENSP00000483244.1

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13363 AN: 151800 Hom.: 1142 Cov.: 32

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.0785

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0687

Gnomad OTH AF: 0.0803

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

GnomAD4 genome AF: 0.0880 AC: 13368 AN: 151918 Hom.: 1147 Cov.: 32 AF XY: 0.0980 AC XY: 7277 AN XY: 74250

African (AFR) AF: 0.0167 AC: 695 AN: 41508

American (AMR) AF: 0.204 AC: 3098 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.0785 AC: 272 AN: 3464

East Asian (EAS) AF: 0.309 AC: 1588 AN: 5132

South Asian (SAS) AF: 0.168 AC: 812 AN: 4830

European-Finnish (FIN) AF: 0.194 AC: 2053 AN: 10590

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4663 AN: 67886

Other (OTH) AF: 0.0814 AC: 171 AN: 2102

Alfa AF: 0.0958 Hom.: 1352

Bravo AF: 0.0884

Asia WGS AF: 0.248 AC: 860 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.49
DANN	Benign	0.65
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1938526; hg19: chr10-62300383;