rs139092048

Variant names:

• chr10-60059785-C-A
• rs139092048
• ENST00000373827.6:c.4960G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001204404.2(ANK3):​c.4981G>T​(p.Asp1661Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,614,234 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (30 hom.)
• Consequence: ANK3 NM_001204404.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.30
• Publications: 15 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)

ENSG00000232682 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068682134).
• BP6: Variant 10-60059785-C-A is Benign according to our data. Variant chr10-60059785-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1711257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00363 (553/152372) while in subpopulation NFE AF = 0.00611 (416/68040). AF 95% confidence interval is 0.00563. There are 3 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204404.2. 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.12596-355G>T		intron	N/A	NP_066267.2
	ANK3	NM_001204404.2		c.4981G>T	p.Asp1661Tyr	missense	Exon 40 of 44	NP_001191333.1	Q12955-4
	ANK3	NM_001320874.2		c.4978G>T	p.Asp1660Tyr	missense	Exon 39 of 43	NP_001307803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANK3	ENST00000373827.6	TSL:1	c.4960G>T	p.Asp1654Tyr	missense	Exon 40 of 44	ENSP00000362933.2	Q12955-5
	ANK3	ENST00000355288.6	TSL:1	c.2380G>T	p.Asp794Tyr	missense	Exon 17 of 21	ENSP00000347436.2	Q12955-6
	ANK3	ENST00000280772.7	TSL:1 MANE Select	c.12596-355G>T		intron	N/A	ENSP00000280772.1	Q12955-3

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152254 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00405 AC: 1017 AN: 251130 AF XY: 0.00401

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00586 AC: 8565 AN: 1461862 Hom.: 30 Cov.: 31 AF XY: 0.00569 AC XY: 4140 AN XY: 727236

African (AFR) AF: 0.00131 AC: 44 AN: 33480

American (AMR) AF: 0.00203 AC: 91 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 291 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00684 AC: 7610 AN: 1111992

Other (OTH) AF: 0.00642 AC: 388 AN: 60396

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152372 Hom.: 3 Cov.: 33 AF XY: 0.00325 AC XY: 242 AN XY: 74508

African (AFR) AF: 0.00123 AC: 51 AN: 41598

American (AMR) AF: 0.00209 AC: 32 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00611 AC: 416 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00542 Hom.: 3

Bravo AF: 0.00396

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00380 AC: 462

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ANK3-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.73	T
PhyloP100		3.3
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.096	T
Sift4G	Benign	0.094	T
Vest4		0.42
MVP		0.55
ClinPred		0.017	T
GERP RS		5.8
PromoterAI		-0.018	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139092048; hg19: chr10-61819543;