4-69944943-G-C

Variant names:

• chr4-69944943-G-C
• rs149927680
• NM_001890.2:c.496G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001890.2(CSN1S1):​c.496G>C​(p.Asp166His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,612,650 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: CSN1S1 NM_001890.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.274

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057938397).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSN1S1	NM_001890.2	c.496G>C	p.Asp166His	missense_variant	Exon 15 of 16	ENST00000246891.9	NP_001881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSN1S1	ENST00000246891.9	c.496G>C	p.Asp166His	missense_variant	Exon 15 of 16	1	NM_001890.2	ENSP00000246891.4

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 151744 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

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: 0.0000147

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000478 AC: 119 AN: 248816 Hom.: 1 AF XY: 0.000407 AC XY: 55 AN XY: 134990

Gnomad AFR exome AF: 0.00731

Gnomad AMR exome AF: 0.000116

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1460790 Hom.: 4 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 726714

Gnomad4 AFR exome AF: 0.00946

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.00218 AC: 331 AN: 151860 Hom.: 2 Cov.: 32 AF XY: 0.00200 AC XY: 148 AN XY: 74184

Gnomad4 AFR AF: 0.00763

Gnomad4 AMR AF: 0.000591

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.00237

ESP6500AA AF: 0.00756 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000554 AC: 67

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;.;.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.65	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Benign	0.053
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.33
MVP		0.40
MPC		0.27
ClinPred		0.12	T
GERP RS		-3.6
Varity_R		0.11
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149927680; hg19: chr4-70810661;