8-2949320-T-C

Position:

• chr8-2949320-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033225.6(CSMD1):​c.10381A>G​(p.Lys3461Glu) 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. 12/19 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: not found (cov: 32)
• Consequence: CSMD1 NM_033225.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

Genes affected

CSMD1 (HGNC:14026): (CUB and Sushi multiple domains 1) Predicted to act upstream of or within several processes, including learning or memory; mammary gland branching involved in pregnancy; and reproductive structure development. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC105377785 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27503794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSMD1	NM_033225.6	c.10381A>G	p.Lys3461Glu	missense_variant	68/70	ENST00000635120.2	NP_150094.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSMD1	ENST00000635120.2	c.10381A>G	p.Lys3461Glu	missense_variant	68/70	5	NM_033225.6	ENSP00000489225.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.10381A>G (p.K3461E) alteration is located in exon 68 (coding exon 68) of the CSMD1 gene. This alteration results from a A to G substitution at nucleotide position 10381, causing the lysine (K) at amino acid position 3461 to be replaced by a glutamic acid (E). 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	Benign	0.25
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T;.;D;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.29	.;N;.;.;N;.
REVEL	Benign	0.095
Sift	Uncertain	0.011	.;D;.;.;D;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		0.45	.;.;.;.;B;B
Vest4		0.53, 0.58, 0.49, 0.50, 0.51
MutPred		0.25		.;.;.;.;Loss of methylation at K3462 (P = 0.0042);Loss of methylation at K3462 (P = 0.0042);
MVP		0.46
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.46
gMVP		0.40

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: rs1285346550; hg19: chr8-2806842;