4-69934701-G-C

Variant names:

• chr4-69934701-G-C
• NM_001890.2:c.96G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001890.2(CSN1S1):​c.96G>C​(p.Glu32Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29

Genes affected

CSN1S1 (HGNC:2445): (casein alpha s1) Predicted to be involved in response to dehydroepiandrosterone; response to estradiol; and response to steroid hormone. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045418352).
• BP6: Variant 4-69934701-G-C is Benign according to our data. Variant chr4-69934701-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3078257.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2	c.96G>C	p.Glu32Asp	missense_variant	Exon 4 of 16	ENST00000246891.9	NP_001881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9	c.96G>C	p.Glu32Asp	missense_variant	Exon 4 of 16	1	NM_001890.2	ENSP00000246891.4
CSN1S1	ENST00000507772.5	c.96G>C	p.Glu32Asp	missense_variant	Exon 3 of 14	5		ENSP00000427490.1
CSN1S1	ENST00000507763.5	c.96G>C	p.Glu32Asp	missense_variant	Exon 3 of 14	5		ENSP00000422611.1
CSN1S1	ENST00000505782.5	c.96G>C	p.Glu32Asp	missense_variant	Exon 3 of 13	5		ENSP00000426684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.011
DANN	Benign	0.17
DEOGEN2	Benign	0.029	T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.36	T;T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.045	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.059
MutPred		0.17		Loss of glycosylation at S34 (P = 0.1243);Loss of glycosylation at S34 (P = 0.1243);Loss of glycosylation at S34 (P = 0.1243);Loss of glycosylation at S34 (P = 0.1243);
MVP		0.17
MPC		0.032
ClinPred		0.037	T
GERP RS		-2.2
Varity_R		0.037
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-70800419;