NM_178123.5:c.1955C>T

Variant names:

• chr2-179112730-G-A
• rs1374699765
• NM_178123.5:c.1955C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178123.5(SESTD1):​c.1955C>T​(p.Pro652Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SESTD1 NM_178123.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• Publications: 0 publications found

Genes affected

SESTD1 (HGNC:18379): (SEC14 and spectrin domain containing 1) Enables phosphatidylinositol-3,4-bisphosphate binding activity and phospholipid binding activity. Involved in negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel. Located in intermediate filament cytoskeleton. Colocalizes with calcium channel complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178123.5. 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
	SESTD1	NM_178123.5	MANE Select	c.1955C>T	p.Pro652Leu	missense	Exon 17 of 18	NP_835224.3	Q86VW0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SESTD1	ENST00000428443.8	TSL:1 MANE Select	c.1955C>T	p.Pro652Leu	missense	Exon 17 of 18	ENSP00000415332.2	Q86VW0
	SESTD1	ENST00000949563.1		c.1970C>T	p.Pro657Leu	missense	Exon 17 of 18	ENSP00000619622.1
	SESTD1	ENST00000854639.1		c.1955C>T	p.Pro652Leu	missense	Exon 18 of 19	ENSP00000524698.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458934 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725796

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111574

Other (OTH) AF: 0.0000166 AC: 1 AN: 60340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000336 Hom.: 0

Bravo AF: 0.00000756

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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.46		Gain of catalytic residue at P652 (P = 0.0573)
MVP		0.32
MPC		1.6
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.42
gMVP		0.45
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs1374699765; hg19: chr2-179977457;