1-201490242-C-G

Variant names:

• chr1-201490242-C-G
• rs770172252
• NM_004078.3:c.215G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004078.3(CSRP1):​c.215G>C​(p.Gly72Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: CSRP1 NM_004078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

CSRP1 (HGNC:2469): (cysteine and glycine rich protein 1) This gene encodes a member of the cysteine-rich protein (CSRP) family. This gene family includes a group of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this gene product occurs in proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSRP1	NM_004078.3	c.215G>C	p.Gly72Ala	missense_variant	Exon 3 of 6	ENST00000340006.7	NP_004069.1
CSRP1	NM_001193571.2	c.215G>C	p.Gly72Ala	missense_variant	Exon 3 of 6		NP_001180500.1
CSRP1	NM_001193572.2	c.215G>C	p.Gly72Ala	missense_variant	Exon 3 of 6		NP_001180501.1
CSRP1	NM_001193570.2	c.215G>C	p.Gly72Ala	missense_variant	Exon 3 of 6		NP_001180499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSRP1	ENST00000340006.7	c.215G>C	p.Gly72Ala	missense_variant	Exon 3 of 6	1	NM_004078.3	ENSP00000345079.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251432 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.0000784 AC XY: 57 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215G>C (p.G72A) alteration is located in exon 3 (coding exon 2) of the CSRP1 gene. This alteration results from a G to C substitution at nucleotide position 215, causing the glycine (G) at amino acid position 72 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T;T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;.;.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;M;.;M;M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;.
Polyphen		1.0	D;D;.;D;D;.;.
Vest4		0.75
MutPred		0.21		Loss of catalytic residue at P68 (P = 0.0741);Loss of catalytic residue at P68 (P = 0.0741);Loss of catalytic residue at P68 (P = 0.0741);Loss of catalytic residue at P68 (P = 0.0741);Loss of catalytic residue at P68 (P = 0.0741);.;.;
MVP		0.99
MPC		0.85
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs770172252; hg19: chr1-201459370; COSMIC: COSV100384677;