NM_001822.7:c.1342G>A

Variant names:

• chr2-174800154-C-T
• rs755106615
• NM_001822.7:c.1342G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001822.7(CHN1):​c.1342G>A​(p.Val448Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,411,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CHN1 NM_001822.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

Genes affected

CHN1 (HGNC:1943): (chimerin 1) This gene encodes GTPase-activating protein for ras-related p21-rac and a phorbol ester receptor. It is predominantly expressed in neurons, and plays an important role in neuronal signal-transduction mechanisms. Mutations in this gene are associated with Duane's retraction syndrome 2 (DURS2). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

CHN1 Gene-Disease associations (from GenCC):

• Duane retraction syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Duane retraction syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2662 (below the threshold of 3.09). Trascript score misZ: 1.5101 (below the threshold of 3.09). GenCC associations: The gene is linked to Duane retraction syndrome, Duane retraction syndrome 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39829737).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001822.7. 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
	CHN1	NM_001822.7	MANE Select	c.1342G>A	p.Val448Met	missense	Exon 13 of 13	NP_001813.1	P15882-1
	CHN1	NM_001371514.1		c.1393G>A	p.Val465Met	missense	Exon 13 of 13	NP_001358443.1
	CHN1	NM_001371513.1		c.1342G>A	p.Val448Met	missense	Exon 14 of 14	NP_001358442.1	P15882-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHN1	ENST00000409900.9	TSL:1 MANE Select	c.1342G>A	p.Val448Met	missense	Exon 13 of 13	ENSP00000386741.4	P15882-1
	CHN1	ENST00000295497.13	TSL:1	c.967G>A	p.Val323Met	missense	Exon 7 of 7	ENSP00000295497.7	P15882-2
	CHN1	ENST00000488080.6	TSL:1	n.985G>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000495 AC: 1 AN: 201878 AF XY: 0.00000934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411898 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 697550

⚠️ 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: 31706

American (AMR) AF: 0.0000261 AC: 1 AN: 38280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22528

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 74244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090746

Other (OTH) AF: 0.00 AC: 0 AN: 58352

⚠️ 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 Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.51		Gain of catalytic residue at V448 (P = 0.0891)
MVP		0.13
MPC		1.0
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.86
Mutation Taster		=50/50

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: rs755106615; hg19: chr2-175664882;