12-51064094-C-A

Variant names:

• chr12-51064094-C-A
• rs369508518
• NM_030809.3:c.1284G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_030809.3(CSRNP2):​c.1284G>T​(p.Leu428Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CSRNP2 NM_030809.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.896
• Publications: 0 publications found

Genes affected

CSRNP2 (HGNC:16006): (cysteine and serine rich nuclear protein 2) The protein encoded by this gene belongs to the CSRNP family of nuclear proteins that share conserved regions, including cysteine- and serine- rich regions, a basic domain, a transcriptional activation domain, and bind the sequence 'AGAGTG', thus have the hallmark of transcription factors. Studies in mice suggest that these genes may have redundant functions. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

LETMD1 (HGNC:24241): (LETM1 domain containing 1) This gene encodes a mitochondrial outer membrane protein. It has a potential role in tumorigenesis, which may result from negative regulation of the p53 tumor suppressor gene. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051180333).
• BS2: High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030809.3. 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
	CSRNP2	NM_030809.3	MANE Select	c.1284G>T	p.Leu428Phe	missense	Exon 5 of 5	NP_110436.1	Q9H175
	LETMD1	NM_001351337.2		c.544-3168C>A		intron	N/A	NP_001338266.1
	CSRNP2	NR_045072.2		n.1738G>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSRNP2	ENST00000228515.6	TSL:1 MANE Select	c.1284G>T	p.Leu428Phe	missense	Exon 5 of 5	ENSP00000228515.1	Q9H175
	CSRNP2	ENST00000863897.1		c.1284G>T	p.Leu428Phe	missense	Exon 6 of 6	ENSP00000533956.1
	CSRNP2	ENST00000863898.1		c.1284G>T	p.Leu428Phe	missense	Exon 6 of 6	ENSP00000533957.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251440 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.90
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.044
Sift	Uncertain	0.023	D
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.47		Gain of catalytic residue at V430 (P = 0)
MVP		0.082
MPC		1.1
ClinPred		0.16	T
GERP RS		2.1
Varity_R		0.072
gMVP		0.32
Mutation Taster		=87/13	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: rs369508518; hg19: chr12-51457877;