11-108321329-C-G

Variant names:

• chr11-108321329-C-G
• rs1064793958
• NM_000051.4:c.6481C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_000051.4(ATM):​c.6481C>G​(p.Arg2161Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2161C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.34
• Publications: 2 publications found

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2714587).
• BP6: Variant 11-108321329-C-G is Benign according to our data. Variant chr11-108321329-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1009988.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.6481C>G	p.Arg2161Gly	missense	Exon 45 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6481C>G	p.Arg2161Gly	missense	Exon 46 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-12258G>C		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6481C>G	p.Arg2161Gly	missense	Exon 45 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6481C>G	p.Arg2161Gly	missense	Exon 46 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1545C>G		non_coding_transcript_exon	Exon 43 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia-telangiectasia syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.76
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-2.6	N
PhyloP100		7.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.75		Loss of methylation at K2160 (P = 0.033)
MVP		0.59
MPC		0.16
ClinPred		0.58	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.31
Mutation Taster		=68/32	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: rs1064793958; hg19: chr11-108192056;