rs117138204

Positions:

• chr10-60208183-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020987.5(ANK3):​c.1047C>T​(p.Cys349Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,614,104 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (55 hom.)
• Consequence: ANK3 NM_020987.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.184

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-60208183-G-A is Benign according to our data. Variant chr10-60208183-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-60208183-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00567 (864/152296) while in subpopulation AMR AF= 0.00713 (109/15294). AF 95% confidence interval is 0.00604. There are 4 homozygotes in gnomad4. There are 380 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANK3	NM_020987.5	c.1047C>T	p.Cys349Cys	synonymous_variant	10/44	ENST00000280772.7	NP_066267.2
ANK3	NM_001204404.2	c.996C>T	p.Cys332Cys	synonymous_variant	10/44		NP_001191333.1
ANK3	NM_001320874.2	c.1047C>T	p.Cys349Cys	synonymous_variant	10/43		NP_001307803.1
ANK3	NM_001204403.2	c.1029C>T	p.Cys343Cys	synonymous_variant	11/44		NP_001191332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANK3	ENST00000280772.7	c.1047C>T	p.Cys349Cys	synonymous_variant	10/44	1	NM_020987.5	ENSP00000280772.1

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152178 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00630 AC: 1583 AN: 251074 Hom.: 15 AF XY: 0.00620 AC XY: 841 AN XY: 135676

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00793

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00641 AC: 9367 AN: 1461808 Hom.: 55 Cov.: 31 AF XY: 0.00634 AC XY: 4613 AN XY: 727220

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.0210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.00301

Gnomad4 NFE exome AF: 0.00678

Gnomad4 OTH exome AF: 0.00818

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152296 Hom.: 4 Cov.: 33 AF XY: 0.00510 AC XY: 380 AN XY: 74466

Gnomad4 AFR AF: 0.00464

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00637

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00703 Hom.: 0

Bravo AF: 0.00586

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ANK3: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.8
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs117138204; hg19: chr10-61967941; COSMIC: COSV55063824;