chr4-2081690-G-C

Variant names:

• chr4-2081690-G-C
• rs369614779
• NM_181808.4:c.2251C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181808.4(POLN):​c.2251C>G​(p.His751Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLN NM_181808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

POLN (HGNC:18870): (DNA polymerase nu) This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5' exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit. [provided by RefSeq, Dec 2014]

ENSG00000290263 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1437341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLN	NM_181808.4	c.2251C>G	p.His751Asp	missense_variant	Exon 22 of 26	ENST00000511885.6	NP_861524.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLN	ENST00000511885.6	c.2251C>G	p.His751Asp	missense_variant	Exon 22 of 26	5	NM_181808.4	ENSP00000435506.1
ENSG00000290263	ENST00000672725.1	n.*571C>G		non_coding_transcript_exon_variant	Exon 18 of 19			ENSP00000500518.1
ENSG00000290263	ENST00000672725.1	n.*571C>G		3_prime_UTR_variant	Exon 18 of 19			ENSP00000500518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2251C>G (p.H751D) alteration is located in exon 20 (coding exon 20) of the POLN gene. This alteration results from a C to G substitution at nucleotide position 2251, causing the histidine (H) at amino acid position 751 to be replaced by an aspartic acid (D). 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	0.089
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.51	T;.
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	-1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.13	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0	B;B
Vest4		0.42
MVP		0.59
MPC		0.10
ClinPred		0.055	T
GERP RS		3.4
Varity_R		0.28
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs369614779; hg19: chr4-2083417;