rs746330303

Variant names:

• chr1-33013271-G-A
• rs746330303
• NM_001625.4:c.630C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-33013271-G-A
• chr1-33013271-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001625.4(AK2):​c.630C>T​(p.Ile210Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AK2 NM_001625.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.138
• Publications: 5 publications found

Genes affected

AK2 (HGNC:362): (adenylate kinase 2) Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Mutations in this gene are the cause of reticular dysgenesis. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 1 and 2.[provided by RefSeq, Nov 2010]

AK2 Gene-Disease associations (from GenCC):

• reticular dysgenesis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000236065 (HGNC:58388):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 1-33013271-G-A is Benign according to our data. Variant chr1-33013271-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 529735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.138 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001625.4. 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
	AK2	NM_001625.4	MANE Select	c.630C>T	p.Ile210Ile	synonymous	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319141.3		c.630C>T	p.Ile210Ile	synonymous	Exon 6 of 8	NP_001306070.1	F8W1A4
	AK2	NM_013411.5		c.630C>T	p.Ile210Ile	synonymous	Exon 6 of 7	NP_037543.1	P54819-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.630C>T	p.Ile210Ile	synonymous	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000373449.7	TSL:1	c.630C>T	p.Ile210Ile	synonymous	Exon 6 of 7	ENSP00000362548.2	P54819-2
	AK2	ENST00000354858.11	TSL:1	c.504C>T	p.Ile168Ile	synonymous	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 45 AN: 144128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.000139

Gnomad ASJ AF: 0.000300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.000408

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000247

Gnomad OTH AF: 0.000512

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250448 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000365 AC: 52 AN: 1423174 Hom.: 0 Cov.: 34 AF XY: 0.0000339 AC XY: 24 AN XY: 708852

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

African (AFR) AF: 0.00 AC: 0 AN: 32866

American (AMR) AF: 0.00 AC: 0 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39222

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84414

European-Finnish (FIN) AF: 0.000628 AC: 29 AN: 46184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000157 AC: 17 AN: 1085546

Other (OTH) AF: 0.0000676 AC: 4 AN: 59192

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000141554), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000312 AC: 45 AN: 144236 Hom.: 0 Cov.: 32 AF XY: 0.000371 AC XY: 26 AN XY: 70046

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

African (AFR) AF: 0.000483 AC: 19 AN: 39322

American (AMR) AF: 0.000139 AC: 2 AN: 14392

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 1 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 4932

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4540

European-Finnish (FIN) AF: 0.000408 AC: 4 AN: 9810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000247 AC: 16 AN: 64780

Other (OTH) AF: 0.000507 AC: 1 AN: 1972

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00154 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	AK2-related disorder (1)
-	-	1	not provided (1)
-	-	1	Reticular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.3
DANN	Benign	0.86
PhyloP100		0.14
Mutation Taster		=88/12	polymorphism

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: rs746330303; hg19: chr1-33478872; COSMIC: COSV61468263; COSMIC: COSV61468263;