10-60196628-GAAA-GAA

Variant names:

• chr10-60196628-GA-G
• rs34796699
• NM_020987.5:c.1690-4delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020987.5(ANK3):​c.1690-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,225,208 control chromosomes in the GnomAD database, including 37 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 28)
  • Exomes 𝑓: 0.020 (26 hom.)
• Consequence: ANK3 NM_020987.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.469
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), 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 -10 ACMG points.

• BP6: Variant 10-60196628-GA-G is Benign according to our data. Variant chr10-60196628-GA-G is described in ClinVar as Benign. ClinVar VariationId is 1174830.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0103 (1370/133074) while in subpopulation SAS AF = 0.0166 (70/4206). AF 95% confidence interval is 0.0135. There are 11 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,Unknown,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	NM_020987.5	MANE Select	c.1690-4delT		splice_region intron	N/A	NP_066267.2
	ANK3	NM_001204404.2		c.1639-4delT		splice_region intron	N/A	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.1690-4delT		splice_region intron	N/A	NP_001307803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.1690-4delT		splice_region intron	N/A	ENSP00000280772.1	Q12955-3
	ANK3	ENST00000373827.6	TSL:1	c.1672-4delT		splice_region intron	N/A	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000503366.6	TSL:2	c.1639-4delT		splice_region intron	N/A	ENSP00000425236.1	Q12955-4

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1368 AN: 133040 Hom.: 11 Cov.: 28

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00698

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.00767

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00612

Gnomad OTH AF: 0.0107

GnomAD2 exomes AF: 0.0552 AC: 6239 AN: 113098 AF XY: 0.0551

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.0419

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0417

Gnomad FIN exome AF: 0.0696

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0491

GnomAD4 exome AF: 0.0200 AC: 21819 AN: 1092134 Hom.: 26 Cov.: 21 AF XY: 0.0204 AC XY: 11153 AN XY: 547070

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0207 AC: 533 AN: 25728

American (AMR) AF: 0.0224 AC: 704 AN: 31448

Ashkenazi Jewish (ASJ) AF: 0.0633 AC: 1286 AN: 20300

East Asian (EAS) AF: 0.0128 AC: 413 AN: 32278

South Asian (SAS) AF: 0.0317 AC: 2074 AN: 65372

European-Finnish (FIN) AF: 0.0283 AC: 1001 AN: 35426

Middle Eastern (MID) AF: 0.0330 AC: 150 AN: 4540

European-Non Finnish (NFE) AF: 0.0176 AC: 14597 AN: 831336

Other (OTH) AF: 0.0232 AC: 1061 AN: 45706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0103 AC: 1370 AN: 133074 Hom.: 11 Cov.: 28 AF XY: 0.0116 AC XY: 740 AN XY: 63838

African (AFR) AF: 0.0133 AC: 493 AN: 37134

American (AMR) AF: 0.00698 AC: 91 AN: 13044

Ashkenazi Jewish (ASJ) AF: 0.0526 AC: 168 AN: 3192

East Asian (EAS) AF: 0.00769 AC: 36 AN: 4680

South Asian (SAS) AF: 0.0166 AC: 70 AN: 4206

European-Finnish (FIN) AF: 0.0161 AC: 113 AN: 7012

Middle Eastern (MID) AF: 0.0187 AC: 5 AN: 268

European-Non Finnish (NFE) AF: 0.00612 AC: 373 AN: 60966

Other (OTH) AF: 0.0117 AC: 21 AN: 1790

Alfa AF: 0.0220 Hom.: 21

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34796699; hg19: chr10-61956386; COSMIC: COSV55054926;